The ApoE4.Info Podcast

Dr. Dayan Goodenowe joins Julie Gregory to announce the opening of his recovery and rehab clinic for dementia patients in Canada. He likens the therapeutic process used by his team as being similar to that used for addiction patients with the goal of improved mental acuity, mobility and mood. They intensively focus on nutrition, exercise, mindfulness and lifestyle management, and the importance of continuity of newly learned habits with supportive follow-up when patients return back home. He describes cognitive improvements that he has seen in his own family members who have used this approach. Dr. Goodenowe also describes an N=1 experiment that he ran on himself using high dose plasmalogens and other supplements to reverse the effects of acute stress with remarkable volumetric gains as evidenced by brain imaging. He discusses how he uses the ProdromeScan, a blood test, to guide treatment and assess progress. Finally, they discuss the upcoming launch of the ApoE4.Info MOD4 Project that will use the ProdromeScan to enable members to track their health progress over time.

00:00:26 Julie

So welcome, Dayan – thank you so much for joining us again. We’re so excited to have you.

00:00:32 Dayan

Thank you, Julie. Happy to be here. It’s been many, many years now. We’ve been working together.

00:00:36 Julie

I know I was looking at that. Our community has actually been working with you for four years now.

00:00:44 Dayan

Pretty excited.

00:00:44 Julie

So it’s been our honor. And thank you so much. Yeah, you’ve been guiding lots of people and helping lots of people get better. So thank you. Since we last spoke, you have opened a dementia rehab and recovery program and I’m so excited to learn more about that.

00:01:04 Dayan

Well, this really comes. You know, I talk about it first in my book. So the last chapter of Breaking Alzheimer’s deals with this community based model of how the current infrastructure really isn’t designed to treat or to deal with complex diseases like dementia, right? And dementia prevention, recovery, rehabilitation. And most of the clinical work that we do around the world are really isolated. We take one agent, we look at B vitamins or we look at a drug and the purpose of those programs is to evaluate a particular agent, right, whether it be a drug or a lifestyle factor. And the goal is to isolate it from everything else. And the person in that type of trial really is a Guinea pig in it, right? It’s not really about that person. It’s about whatever agent you’re testing.

And we wanna flip that. There’s so many validated programs that work, and dementia recovery requires people who want to [get better] so we can focus on a caregiver and dementia individual that are serious about getting better, and we take an integrated approach and it’s really self focus on the individual.

So we do get advanced nutrition … So first of all we have a place for them to go. It’s a quiet, serene 10 acre facility, full facilities there with a lake in a peaceful environment, in Moose Jaw, Saskatchewan, which no one has ever heard of, but it’s very, very nice.

00:02:37 Julie

It’s in Regina, right?

00:02:40 Dayan

It’s near Regina, the city is actually called Moose Jaw.

00:02:43 Julie

Ohh Moose Jaw. Very very cool.

00:02:46 Dayan

Yes, the town that gets made fun of all the time in certain movies. But anyway, it’s not a medical program. We take a kind of a drugs of abuse model to this, right. So say you are a drug user and you want to get off of drugs, you can’t do it living in the wrong environment. So this allows people to come to a proper facility and it’s really them, it’s their program and it’s all designed for that individual to see themselves, the mobility, their cognition, their lifestyle, their diet and also prepare them to go back home.

So there’s three months where they can stay in facility. We do advanced blood work, obviously the supplementation protocols … so we look at dementia and brain structure recovery, and it is a recoverable situation and people do recover from cognitive impairment. That’s a fact.

OK, whether or not you have these big long randomized clinical trials that says this pill statistically improves cognition, that doesn’t change the fact that people do physically get better. It’s documented over and over and over again.

00:03:54 Julie

Yes, we see that all the time, absolutely.

00:03:57 Dayan

So the point is how do you do that in your personal life? It’s not about validating some drug company’s drug. And there are certain things that we know for a fact have contributing factors to that. So on the biochemistry side, we know the plasmalogens are contributing to mental health and brain restoration. There’s a huge amount of evidence of that. Proper B vitamin usage is another big issue, right? It’s just been there forever. People forget that it’s actually important to do it right. Your mitochondrial function. Those are basic biochemistry things that have an impact. And people need an ability to do that for themselves, so this is this is self-directed research.

00:04:42 Julie

You know what? I just want to jump in before you go any further because you have really hit the nail on the head. You need somebody who’s motivated to get better, and I love that your program is focused on that and that you also include a care partner because at the beginning they won’t be able to do all these strategies by themselves and they are gonna need someone to work with them. So I think that’s beautiful and …

00:05:11 Dayan

… and you want to prepare them to go home again!

00:05:13 Julie

Oh, I love that. So, yeah, this is the era of treatable dementia. That is huge. That is huge. Go on.

00:05:22 Dayan

Yeah, and so on the biochemistry side, that’s straightforward. Those are, you know, there’s no ambiguity there. Now what which particular piece will make the biggest contribution to an individual? That’s gonna be individual specific, but we know collectively these things will have impacts, but it’s just well known.

And then on the lifestyle side, you know the diet, obviously the time restricted eating, proper types of foods at proper  times. But you don’t need to be depriving yourself. You can have real meals. It just has to be with the right content. And also people don’t know how to cook, or they don’t know how to shop. So this facility is not a luxury camp. It’s a working camp, it’s boot camp. People, they go grocery shopping with us. And we get food and we cook food in the facility and the catering facility. They have their own room. They have their own privacy, all that stuff. It’s actually designed that way. And creating a daily lifestyle, because each day has to be reward driven, right? So you have to have a purpose.

So physiologically, skeletal muscle mass is one of the biggest things people need to deal with. They need to do resistance training. They need to incorporate into their lifestyle the rebuilding of skeletal muscle mass because of sarcopenia. That’s the biggest issue. It drives 99% of all diabetes, just loss of muscle mass, OK. And in the elderly, we mistreat these things. And so exercise and then the routine of your day gets into place.

And then the next part is the mindfulness part of it, because you have to have purpose. One of the problems with getting older is that people lose purpose. OK, a lot of the things that keep us healthy, we consider stressful or bad. Well, I can’t wait to not do that. But a lot of those things actually kept you alive. It gave you a reason to get up in the morning. So when we look at these things in the world where social activities and people involved in social activities have positive impacts on their health, it’s not the social activity itself. It’s getting up. It’s doing your hair. It’s getting dressed. It’s actually going out for a real meal rather than eating something at home. It’s all the things that surround that social environment that actually are the health inducing parts of the social interaction, you know, association with improved health.

So just like in a drugs of abuse kind of situation, you need to create new habits and then reinforce those habits. So in the facility you’re there for three months. And you have time to build a pattern in a relaxed environment. So we’ll do a cardiovascular test and we’ll put a 24 hour Holter monitor you because we know cardiovascular heart improves. We measure spirometry of your lung function. We’ll measure vision. We’ll measure auditory stimuli. We do real life stair climbing, like, can you can you climb up the set of stairs? What’s your mobility now? What’s your mobility later? Because if you’re gonna live a healthy life, you need to be able to do these things. And we call it the three M’s of a life worth living, right?

00:09:15 Julie

Right, we all need a reason to get out of bed in the morning and it’s easy when you’re working, right? But not so easy when you retire.

00:09:25 Dayan

Correct! And so then they have to have a plan for that.

So, we have a fieldhouse with exercise and track and field and places for people to go. But then while they’re here for three months, they have to say, OK, what am I gonna do when I go home? Where are you gonna get your hair done?  Where are you gonna go for exercise? Like, what are you gonna do with your day?

You’re gonna create a pattern – this is what my days deal with. And then you program that, you say, OK, let me prepare [a plan] for going home that I can read. And then we’ll have nine months where we follow up and check up and harass you basically for that time to get that pattern in your life and then we can do maintenance after that.

00:10:05 Julie

I love that. I love that you focus on the three things and you just keep it simple. Mental acuity, mobility and mood, and you just distill it down to that. But you’re right, that’s everything.

00:10:19 Dayan

And it’s for the person.

00:10:19 Julie

As you age, yes.

00:10:21 Dayan

So we we videotape the individual for their purpose. So we’ll do the 8S cog. We’ll do pegboards. We’ll do all the traditional classic validated clinical trial metrics, but they’re not for us – they’re for them. They can look at themselves and because people forget – this is what we’ve learned over the last few years – they start getting better, but they don’t really remember. They can’t really see the difference in themselves, and we see a lot of this when people stop doing something and then they regress. We find far more people recognizing improvement upon regression than improvement upon improvement – all the time, we see that.

00:10:59 Julie

I see that – you see that with my mother, yeah.

I’ve got a question. So do you have a cut off in terms of cognitive impairment?

00:11:11 Dayan

Not really. If you look at the clinical dementia rating scale, we’re going to be in that one to two, what we’re targeting.

People that are six months to 12 months from going into long term care, where the where the caregiver is saying, I’m almost at my wits end. I’m doing everything I can, OK? I don’t really want to put my my loved one into, you know, mental memory facility, but I’m gonna go crazy if I don’t myself. OK, so we want to find that group of people that are kind of in that six month to a year pre memory care. We want them mobile.

They should have some level of mobility, but we are flexible for things and that’s the target population because our goal is to get to people before they’re they’re getting into long term care. We reenergize them, restore health as much as we can and then create an environment that they can live for a very long period of time prior.

So we wanna prevent that long term care admission is really the biggest goal there.

00:12:15 Julie

And are you able to return people to live independently who weren’t able to do that before?

00:12:24 Dayan

Well, we’re just starting like we have anecdotal experience of people that aren’t in the program because the very first participants just came in at the beginning of August. And the second and third groups … it only holds 18 people and we only take we only take six people a month, so it’s not a warehouse facility, right – it’s an intimate facility.

So you get 6 people per month coming. And they’re there for three months. So basically every month, there’s six people coming in. There’s six people going home again, and then we’re offering … we’re working on a kind of a weekend day program here in the Temecula facility and Moose Jaw facility where people can come in for the day and then go home.

So our truncated process … the Moose Jaw facility is in house – you basically come and live there for three months and get things organized in your life. The other here in Temecula and Moose Jaw will also have like kind of like a weekend retreat model where people can come in for a day, get some stuff done, get some blood work done, get some supplements, get some assessments done and then kind of have a homework assignment, if you will, and then they can come back on a recurring basis.

And then we’ll have different levels of you know, cuz the goal is to help people, right? And so we have to understand, we have to tailor things for that individual because everyone’s life situation is slightly different.

00:13:54 Julie

Absolutely. So for the in-house facility, do you mind if I ask what the cost of that is?

00:14:00 Dayan

Yeah, it’s going to be for an entire year’s program. It’s going to be just under 100 grand. And so we are right now since we’re doing the opening, there’s a short term window where people can come in for 49 grand. It covers both the caregiver and the [care partner], so it’s actually very, very inexpensive. If anyone has ever had to put someone into a memory care facility like I have, this is an extremely discounted price.

We’ve been able to do it in a manner that is cost effective so that it fits people. And so for the first three or four months here, we’re gonna offer the discounted price because you know there are always gonna be some little things to work out and it’s all fully staffed and running, but by the end of December and early January, it’ll be back to the full …

00:14:47 Julie

Around it’s going to be 100,000 for the full year.

00:14:53 Dayan

Yeah, three months in facility, nine months at home, all your supplements, all your everything included, all supplements, food, lodging. Only thing’s not covered is your travel back and forth basically.

00:15:04 Julie

And that’s your support for the nine months afterwards as well. That sounds wonderful. I would imagine you have a waiting list. Am I correct?

00:15:14 Dayan

It’s getting there. It’s getting there. We’ve been very careful not to … like you’re really one of the first people that is kind of publicly … we sent it out to some of our doctors and and so we’re just kind of going slow because we’re getting …

00:15:24 Julie

OK.

00:15:26 Dayan

So we haven’t really gone large on this thing because we’re still working on it.

We’re doing some large clinical trial / community trial work that’s gonna plug into this program as well. But yeah, so that’s that’s kind of where it’s at. So yeah, your your timing is pretty amazing, Julie cuz … yeah, your timing is amazing on 2 fronts, not just this clinic.

I’m gonna be presenting real data on the first human taking high dose plasmalogens for 18 or 16 months, which is me. And you’ll be able to see the changes in my brain structure and function on advanced MRI. And so I’m going to be presenting that actually at the the Peptide World Congress on August 19th. So you’ll be able to see that we can actually restore brain structure and volume with plasmalogens using my own brain as an example.

00:16:13 Julie

Wow, do you mind giving us a little preview of that?

00:16:19 Dayan

Well, I don’t have any pictures to share either. But yeah, but the point is that certain cell bodies have increased quite dramatically, basically I’ve reversed over 10 years worth of natural atrophy in 16 months has been completely restored.

00:16:34 Julie

Wow! And when you say high dose, what, what kind it’s prodrome neuro I would assume …

00:16:39 Dayan

Neuro and Glia. So basically we have all this like I’ve been studying these molecules for so many years, right?

And so we’ve done all the animal work. So I’m at about 100 milligrams per kilogram dose. So I take what I took because I do everything on myself before I tell anyone else, and basically I don’t tell anyone anything. I said, “This is what I do. You know, work with our doctors. I always recommend that. We have a huge list of doctors out there that know exactly what they’re doing. But people want to do their own thing. So, like, we can share our own personal experiences. But I take about 5 mils of neuro in the morning and about 5 mils of Glia at night.

00:17:14 Julie

Wow. And that’s versus 1 mil, which is a pretty standard dose of the ProdromeNeuro.

00:17:18 Dayan

Neuro, you know, we have children with rare diseases taking high doses, but this is a pretty good dose. It’s at the upper limit of what we’ve done and I wanted to make sure I use myself as a Guinea pig over the course of a … I’ve been on that for quite a while actually, my dad and other people as well, so.

00:17:35 Julie

And did you feel changes in your own cognition? Did you measure any changes?

00:17:41 Dayan

Not in that regard. It’s just my own life. I’m actually physically stronger than I was in my 20s and 30s. I have better muscle mass. I have better recovery rates. I remember trivia better, so I know these things. I feel more in control of my life. It’s interesting, cuz when I started cuz, you know people, we think researchers … it’s like having a mechanic, right? They drive around in a broken down car. They fix everyone else’s car but their own, right? And so part of this process is my, you know, practicing what I preach and and doing that kind of stuff properly and it’s good cause I definitely had some some health improvements to make on my own. And you can see them happening. Which was great!

00:18:26 Julie

I love and respect that. And you say that your father has been on a similar regimen. Have you seen cognitive improvements there?

00:18:33 Dayan

Ohh yeah, like he said he can. He’s well, I got several family examples and my dad is 86, coming 87. He functions like he’s in his 60s. He’s fully mobile, fully drives. He does maintenance like he’s one of the more active people. I have a hard time keeping up with him. And so he’s a very, very physically active and strong 86-year-old.

00:18:59 Julie

That is beautiful. Was he always that healthy or do you feel like the program you’ve put him on has helped him get there?

00:19:06 Dayan

Ohh, he’s gotten better. He’s always been healthy for the most part.

00:19:09 Dayan

Yeah, but I you know, I used to … we’ve worked together. I’m just a farm boy from the prairies and so, but yeah, so it’s definitely helped. And then my aunt had serious memory loss. She was to the point she couldn’t remember the name of her son, and she now knows everybody. If my dad calls my uncle up, she can hear his voice across the room and say, you know, we’ll announce it and she goes out for dinner and she’s, you know, she still has mobility issues, but basically, she can recite everybody in her 50th wedding anniversary albums and stuff like that, so there’s clear, very clear, unambiguous restoration of memory and function that occurs, and we have lots of stories of this with our doctors and other people, so it is real. It happens and and it’s logical.

00:19:59 Julie

You have a clinical trial published. It is quite successful and it it shows improvement as well.

00:20:06 Dayan

In four months, we had a significant 75% of the people with the clinical dementia rating of two. Improving entire score in a four month period and an escalating dose. So it’s like I tell people all the time – no one thing ever is a silver bullet, OK? It has to be done with other things. You know your lifestyle. Like there, there is no magic to health, OK? It’s just common logical sense. But then it takes consistency and commitment to do things.

00:20:36 Julie

And that’s where you found that the drug rehabilitation model beautifully intercepted because it really does take commitment from the individual to adhere to this new lifestyle.

00:20:50 Dayan

We’re essentially addicted to dying. OK, death is an addiction. Like we we do things that we know exactly are bad for us.

00:20:55 Julie

That’s powerful.

00:20:57 Dayan

Right, like a heroin addict knows they’re a heroin addict. No heroin addict was like, hey, this heroin is good for me. Like, not a single person that’s a drug addict says, this is good stuff. OK, but they know it’s not good for them, but they can’t stop doing it.

00:21:11 Julie

They can’t break the pattern, they just can’t get out.

00:21:15 Dayan

And so if you have type 2 diabetes, you’re not eating, you’re not sleeping … you know that’s not good for you. Like, it’s not rocket science. Like people know health for the most part, but they can’t seem to break those patterns. So fundamentally it’s this inability to stop doing things that we know have negative consequences and so having that reprogramming and resetting and kind of creating a lifestyle that … people need help to get that organized and then but you have to want to, right?

00:21:49 Julie

You have to want to. That’s the most important thing, but I think another huge part of the magic is leaving your current environment and lifestyle and physically going somewhere else for three months. I think that’s super powerful too.

00:22:04 Dayan

It is. It just gets some new environment, clean, clutter free. They can focus on it. There’s not all the distractions of your everyday life, and heck, if you’re there for three months, if you wanna get something installed in your house, if you wanna get, you know, some fans and clean it up, and you can get your family members to start doing some stuff at home. So when you come back, it’s all cleaned up for you, right?

00:22:27 Julie

That is an excellent point. If you don’t mind, I want to dive a little bit deeper. So you mentioned a bunch of strategies that you’re using while people are at your clinic. Would you mind sharing what kind of diet you are using?

00:22:45 Dayan

So the first little while, we don’t want to change. It’s your life, right? So people, your diet and your food is pretty important. You start messing with people’s food and you’re gonna have trouble. And so the first week or so is just kind of getting into the groove of things, right, and then we’ll gradually change your morning to either no breakfast at all or something high protein / fat breakfast, one glycemic meal a day, which is your later meal. And taking time to prepare your meal. Basically, one main meal a day with some snacks. so it would be protein, fat snack like an egg and that comes in the breakfast and evening similar before bed because sometimes you know the fasting, it is … everyone’s different, right and so …

00:23:33 Julie

Ohh it’s tough if you’re insulin resistant, you can’t go to a long daily fast overnight.

00:23:39 Dayan

And if you can’t sleep, then you’re going have to wait. Like some people you can’t sleep if they’re super hungry, so give them something to eat at night that’s not glycemic. And then what we’ll do is we’ll actually shift them to our nutrient drinks like we have egg yolk, oil drinks that contain casein. Or whey in the morning and creatine. We can get a lot of these supplements into a nutrient drink format because that’s the other problem in the elderly, is that – like I take 20 pills a day, but you can’t do that. Kids can’t do that. The elderly can’t do that. The caregivers can’t be … there’s no way they can manage that level of load. So we need to simplify that.

So we’ve been able to develop nutrient drinks that contain egg yolk oil so has nice high quality phosphocholine and lipids.

It’ll have trehalose, which is a non diabetic sugar that helps actually reduce insulin reactivity. We use a whey protein for the mornings. You can use a casein protein at night which gives them better sleep, so there are very strategic, scientifically validated nutrients that we put in. But we put it in slowly.

00:24:45 Julie

And you figured out how to make them taste good, I would imagine.

00:24:49 Dayan

They do, actually. And some sweeteners aren’t that bad for you. You take maple syrup, for example. Maple syrup has a very, very low glycemic index. Like it actually is very little insulin sensitizing molecule. So you can sweeten things up a little bit with certain things. And yeah, it’s very nice. It’s kind of a custardy taste and you can blend it with anything you want to. You can make waffles with it, which I don’t recommend, but you can. Make anything you want with it.

00:25:20 Julie

So it sounds like you’re doing a small breakfast higher in proteins and fat. You’re doing the biggest meal of of the day at lunch when the sun is at its highest peak, which everybody says is something we should all be doing, and then you’re moving to a smaller dinner that’s also low-glycemic?

00:25:39 Dayan

Yeah, well, actually, no. I’m really going to two smaller meals. Then the evening meal is going to be a bit of a bigger meal because there’s cooking and there’s a time … and part of it’s your lifestyle, right? It’s kind of the reward of a day well done. And so you take your time, you relax, you’ve done all your running around for the day. Take the time to prepare a meal. OK, have a decent meal. Finish your day. You got a few hours after that and then it’s more of a satiating for bedtime. And so, you know, have that in that 4:00, 5:00, 6:00 range.

00:26:13 Julie

Got it.

00:26:18 Dayan

Have a kind of a decent decent meal and then kind of have two smaller high protein snacks during the day while you’re out there working.

00:26:25 Julie

Ohh before that and then you do the bigger meal at the end of the day when you’re ready to relax, which is a beautiful pattern for so many of us. I find that’s what I do, yeah.

00:26:34 Dayan

It’s for family time, right? So if you’re out doing things, you prepare the meal, you finish your day … it’s a reward for a day, and each day should be a milestone. Like each day has to feel that you’ve completed a milestone every single day, so there’s not this really, really long delayed gratification concept … like you should have that daily gratification of OK, I finished today. It was a good day.

00:26:58 Julie

I love that. I love having a meal be later in the day, a time when you’re coming together, celebrating the day and spending time with people that you love. So that’s great.

00:27:08 Dayan

And then you start coming down from the day there properly.

00:27:11 Julie

So for that bigger meal, you say it’s the higher glycemic meal then?

00:27:17 Dayan

Well, you’ll still have food like … you’ll have vegetables, basically good quality meat like salmon.

00:27:22 Julie

Sure. Yes.

00:27:23 Dayan

And that’s the other part that we try to get people like, teach people to go get good quality meat and salmon and steak and chicken and and have that good quality. You know, spend the money to get a decent … and so that’s the other part of the whole thing …

00:27:40 Julie

Teaching people how to get wild caught salmon and grass fed beef and …

00:27:43 Dayan

Right. And and have that as a reward. Cause people they really don’t feel that they’re worth it half the time. So there’s a lot of times what they do is they eat like crap because they don’t think they’re worth the extra $10 or $5 for a proper meal at the end of the day. Right? They do! This is a population of people that some of them start feeling that they’re just taking up space in this world. So you have to kind of fix that and say no, you’re valuable. You’re worth being alive. You have something to contribute here. And you’ve earned it basically and so … that’s the kind of concept when people kind of start and … it’s narcissistic, right? It’s about them. It’s like you have to think about yourself, and it’s like the old airplane, put the mask on yourself before you help others, right? Like if you wanna be helpful to your grandkids if you wanna be helpful to your kids. OK, then this is the way to do it.

00:28:43 Julie

Absolutely, they need to put themselves 1st and take take care of themselves.

So going back to that meal – vegetables, healthy proteins … do you restrict carbohydrates at all?

00:28:58 Dayan

Not really as long as it’s part of a balanced meal.

00:28:59 Julie

OK.

00:29:04 Dayan

And it’s gonna be part of that fat – the problem with carbohydrates is when they’re taken all by themselves. And your body does need carbohydrates. You still need it in your body. Your body shouldn’t go without it. Now keto is fine, like more of a time restricted process. And if you use keto specifically for a particular disorder, that’s a different situation, right? But for general health, I think … we can talk about this in much greater detail but … keto is very different. It’s hard to be true keto, to truly change the biochemistry of your body such that you’re not even using [carbohydrate], you’re using ketone bodies […] you have to, you have to block gluconeogenesis to actually get into true keto. And you gotta be very, very careful, because if you’re not doing that, then you’re doing muscle wasting, cause your body will use your protein to create sugar. And so keto has to be done carefully biochemically because keto can create sarcopenia.

00:30:15 Julie

And you’re talking about nutritional ketosis, because I would imagine with the fast that you’re doing in the time restricted eating people are clearly in a mild level of ketosis which is …

00:30:30 Dayan

Well, you’re mild, but you’re you’re in a fasting state. The trick is to be in fatty acid metabolism. OK, that’s the trick cause that’s what makes your steroids. That makes your hormones. It makes your plasmalogen’s. It makes. It’s being in the fasting state. So ketosis means that the body’s not actually making glucose anymore. It’s using ketone bodies. It’s a little bit different. We loosely use these terms and they have different meanings. And if you look at them really closely …

00:31:03 Julie

Sounds like you’re healing people that have an unhealthy metabolism, people that are insulin resistant, by just the time restricted eating, and the healthy meals that they’re being offered and you’re promoting metabolic flexibility as opposed to …

00:31:21 Dayan

Skeletal muscle mass. I’m a broken record on this skeletal muscle mass.

00:31:25 Julie

Well, I want to get into that next.

00:31:25 Dayan

Elderly have to build.

00:31:28 Julie

Yeah, but I I was going to say it sounds like you’re promoting metabolic flexibility. Where they’re naturally moving in and out of burning ketones and glucose as humans were designed to do.

00:31:39 Dayan

Correct, proper daily cycle, yeah.

00:31:40 Julie

Exactly, exactly. So yeah, the next thing I want to talk about is exercise, and I love that you’re a broken record about strength training because it is so important as we age. As a post menopausal woman in my 60s, I strength train almost every day. I love it and I absolutely need to at this point in my life because I find myself losing muscle mass.

00:32:09 Dayan

And you gotta be careful you don’t do it too much … I always tell people it’s recovering from resistance training that you get the benefit from it, not the actual doing of it.

0:32:20 Julie

Right.

00:32:22 Dayan

The doing of it is bad for you. The recovering of it is good for you.

00:32:25 Julie

That’s right. Because you’re breaking down the muscle fibers and the recovery is when the magic happens.

00:32:32 Dayan

And you want to give people time to do that. And so, yeah. So yeah, that’s absolutely true. Because […] diabetes and even cancer, OK. One of the things to happen with cancer is sarcopenia, right, like the people really lose muscle mass … or all of these situations with people getting these massive sicknesses. One of the first things you start losing is muscle mass, and it becomes very, very hard to get it back.

But the big point on the diabetes side is that your muscles are your primary utilizers of fasting triglycerides. OK, so fat is your storage molecule in your fat cells, and if your muscles deteriorate and don’t metabolize fatty acids, your fasting triglycerides are elevated. OK, this is why exercise has such a powerful effect, because … it’s actually that inability to metabolize the fatty acids coming off your fat cells in the fasting state that drives your metabolic syndrome situations and is driven because the balance of your body gets disrupted. OK, as your muscle mass goes down, if your muscles aren’t consuming the triglycerides, the fatty acids, OK, it blocks sugar from coming in, OK. And so that’s why your insulin goes up and your blood glucose goes up, because your muscles aren’t metabolizing the free fatty acids. OK. And why insulin is such a bad thing is because basically you’re forcing cells to take glucose that they don’t want. They’re saying, hey, I’m full. Don’t give me anymore, OK? And so that’s why I’m a broken record on that. But yeah, it’s important, it’s healthy, but you should rest a good day, like a real rest …

00:34:16 Julie

So do you recommend strength training every other day? Is that your ideal?

00:34:21 Dayan

And even taking two days off on the weekend, like, you don’t need to strength train every day. It should go heavy weights, and then rest.

00:34:29 Julie

See, I’m probably not doing as heavy of a weight. I’m fine going lighter. Yeah, and doing it more frequently.

00:34:38 Dayan

No, you should be at 10 reps you know in that range and …

00:34:40 Julie

Ohh yeah. Ohh no. Yeah, I’m I’m well past.

00:34:42 Dayan

Yeah, you should increase your weights until you can do about 10. You should do weights until you can’t do any … like you should do weights to exhaustion and then wait and and take a couple days off. As an anecdotal thing, like I’ve been kind of an athlete all my life. I use this six day routine. I’d have three different workouts and I do them twice a week for six days, right? And I wrote them legs and thighs. Biceps, whatever it is, I can’t remember. Right. And then I got working and I couldn’t do this big, fancy six day routine, right? And so I ended up saying I can’t do this. So I started working out just twice a week, Saturdays and Sundays. I got stronger working out twice a week than I did before when I was working out six days a week and that was my first big wake up call for me in my 30s.

00:35:40 Julie

I love that. And were you working out harder on those two days?

00:35:47 Dayan

About the same.

00:35:48 Julie

About the same.

00:35:50 Dayan

But I did less exercises, obviously. I would just do the core, biceps and triceps and bench presses. But that was shocking to me because after about a couple months I’m bench pressing more, I’m lifting more of my curls and I’m working out less. So I think we we have a lot of overworking.

00:36:12 Julie

Well, that’s probably me because I’m strength training five days a week and I’m doing at least 45 reps of everything and I am going to exhaustion, but I’m never sore. I’m one of those people that I’m very rarely sore, you know.

00:36:30 Dayan

Well, once, once you’re once you’ve got your biochemistry, you shouldn’t be. You should get. You should get a burn. You should feel it actually work.

00:36:36 Julie

Right. Oh, when I’m on my last rep, yeah, I’m done. I literally cannot do anything else. But you’re inspiring me to do less if I can get more of a benefit. And on the off days, I imagine you focus on aerobic exercise.

00:36:53 Dayan

Yeah, gentle walking like you can do a little bit of, you know, good hiking. And obviously if you if you wanna do some, you know, low impact cardio. Absolutely, yeah.

00:37:04 Julie

Like running if you feel like it, but I love interspersing, running with walking, and I love spending time in nature. I mean, independently. That is so healing.

00:37:14 Dayan

Hiking is awesome. Like you’re going up and down the hill. And you have this kind of varied behaviour – your balance gets better because you’re working, you’re on uneven surfaces …

00:37:25 Julie

And your senses are overwhelmed by the beauty and the wonder of nature, and nothing in a gym can replicate that.

00:37:28 Dayan

Yeah, absolutely, yeah.

00:37:34 Julie

Yeah, so that’s that is beautiful.

00:37:34 Dayan

Exactly right.

00:37:37 Julie

And you spoke about mindfulness, which I absolutely love. So many people lead their lives without really paying attention. They’re like on autopilot, and I think mindfulness has to be the core of any behavior change.

00:37:53 Dayan

Well, look, the reality, this is a stark cold reality – stress shrinks your hippocampus. Period. OK. Like it actually physically will shrink your hippocampus, which is your memory center. OK, so managing stress is critical to maintaining long term mental acuity. Like it really is. And actually I’m gonna present that cause I’m doing functional MRI and I can show you how the amygdala activity is dealt with by stress cause I’ve had a bit of a stressful year and it shows up on my MRI, so it’s kind of a wake up call for all of us who think that we’re impervious and we can say, hey, I got it all under control. You may think you have it under control, but you might not. So it is a reality – you have to take stress seriously and you have to learn how to let things go, and mindfulness is amazingly … and the documentation is quite strong in the clinical literature.

00:38:46 Julie

Very strong and it’s something once you understand the philosophy, you can practice it all day long. It’s just catching yourself when your minds wandering and you’re about to go on autopilot and do something you shouldn’t do. Ohh! It’s that aha! moment when you catch yourself, so yeah.

00:39:04 Dayan

And and then mindful awareness is where you get the views like that’s how you redirect your behavior. Say OK, you know what?

00:39:10 Julie

Yes. Yeah. Right. Ohh, that is beautiful. So are there other stress management strategies that you’re using with your participants?

00:39:19 Dayan

Well, they’ll be going through all the training that normally happen, like the Hazelden programs like the Betty Ford type stuff, like all the stuff that are important for self-awareness, self-confidence and life skills training is life skill training. We don’t take things for granted. Like we don’t assume people know how to cook or how to make a meal nutritious. We don’t assume anything … It’s really like a big bed and breakfast at the end of the day … it really is that kind of community setting.

00:39:57 Julie

Or summer camp for adults? Like, I’m like, sign me up. I’m ready to go. I love, I feel like you’re building self-confidence by teaching them to shop, teaching them to cook and prepare wholesome meals. Like you’re giving them their sense of worth back and it’s very sad in society, in Western society, people do not value elderly people. They have so much to give. So much wisdom. So that is beautiful.

00:40:27 Dayan

And we’re very agnostic. I don’t care what part of the program makes someone better. I just care that they get better. OK. It’s not about bragging about one piece of the puzzle … it’s not about the plasmalogen is the silver bullet or the exercise is the silver bullet. It doesn’t matter. The only thing that matters is that the person starts getting better, OK. And how they get better, you know, we’ll document it and we’ll back all this stuff and we wanna show people that this is real. But there’s not a hidden agenda. To the individual? They don’t care. They just want to get better. They want their life to get better, they want their home life. They want to be able to live at home. They want to be able to have a meaningful life. And so in each person, a piece of that protocol is going to have a greater contribution than another, and at the end, I don’t care which one was the biggest contributor.

00:41:22 Julie

Right. Well, that is beautiful. And it sounds like you also are teaching habits. You’re teaching them a healthier routine and sending them home with it so they can replicate it. And you haven’t had the clinic running long enough to know anything about success, but I know you’ll document all of that, hopefully publish it.

00:41:46 Dayan

Ohh yeah, we’ll do all that, and we have larger clinical trials where we’re doing the day program, where people come in, do assessments. Like that’s the trial of over 100 people starting pretty soon. So we’ll do all that work and we’ll do all the community work cause we wanna support these protocols. These are protocols to be emulated, right? Our doctor network … and we’ll work out the bugs.

Even our big, larger autism community, we have almost 800 autistic families now in our private Facebook group, and it’s not the science. It’s the daily implementation. Like how do you actually get an autistic child to take this kind of supplement, and what’s it gonna affect? Is it gonna give them constipation or are there other issues? Like it’s actually not the science – we have more than enough science. The hard part is using it and funding it.

00:42:43 Julie

I love that you recognize that because so many scientists and researchers are out here with their theories, but the devil is in the details and implementation. So to that end, I know you’re training practitioners, but I assume you’re also training health coaches.

00:43:01 Dayan

So it’s pretty well an open tent on our program … we have different levels of of access … we want to make sure we don’t leave anyone between the cracks, if you will. But yeah, it’s … find the right program for you. Obviously we have the early adopters, our high end doctors, the longevity and biohacking community, and they add our plasmalogen and our supplements and our testing into their existing protocols. OK, like we’re not here to tell people what to do. We’re here to help you do whatever you want to do, right, and whatever we can do to to help you succeed and reach your goals, we want to be able to provide services for that. And so you’ll have doctors like our advanced MRI stuff, people doing peptides and exosomes and intracranial ultrasound. And like, there’s a whole bunch of science level stuff that we are involved in, and then it comes down to the more practical side of things and it’s kind of, find your level. We can help you in in your path.

And sometimes maybe it’s just being part of community group like the ApoE4 group, right, where you guys are sharing, right. And we can find a piece we can contribute, and other people are contributing their piece of the pie and collectively, people find things that work for them. And they can find that person and that person’s life that closely emulates their own. And they can say, OK, I get some hints from somebody, and I can try this. And so we all have to be kind of mentors to people that can then self associate with us. Like me – I’m a 54-year-old, generally healthy man, and I wanna stay this way, right? So there’s gonna be other men in my age group, that’re gonna say, OK, like, OK, what’s going on? You know, I like this. I don’t like that. I think that’s a good idea. I think he’s an idiot on this one. Whatever. Right? That’s the conversation. And that’s what we all basically become, you know, mentors and students at the same time.

00:45:17 Julie

Right.

00:45:17 Dayan

In this process.

00:45:19 Julie

And that is a beautiful introduction to our MOD4 project that we’re very close to launching. And for those who aren’t aware, MOD4 stands for Metabolomic Open Access Dataset for the ApoE4.Info community, and we’ve created software on our website where we’ll be able to collect data using your ProdromeScan that will provide ApoE4 carriers (and others because we want a control) to basically track their health progress. And so we’ll be using your ProdromeScan. So can you remind our listeners what the ProdromeScan is?

00:46:03 Dayan

So the ProdromeScan is this 30,000 foot view of your core biochemical systems, and it’s really talking one-on-one with your body. So we deal with the membrane structure – plasmalogens, phosphocholines, the plasmalogen versus the phosphatidyl versions of those molecules, and when you have enough of them in the right proportion.

We look at the fatty acid distribution because there’s a lot of conversations about omega-9, omega-6 omega-3. We actually look at those ratios on the actual phospholipids that are in your body. Like we don’t take your blood and digest it into a soup and give you total fatty acids. You actually understand those fatty acids as they are existing in your membrane lipids.

There’s some gut metabolites called gastrointestinal tract acids that are highly associated with different cancers but also gut health. We look at those molecules.

Methyl transferase system, which is a big deal like your homocysteine system. But we look at it in greater detail, we look at your phosphocholine to ethanolamine ratios and sphingomyelins to ceramides to make sure because sometimes you can go on methyl homocysteine lowering programs, but not actually getting the outcome that you want.

Look at mitochondrial function. Peroxisomal like, that’s the big thing with inflammatory people, especially in today’s day of long COVID and people, you know, getting knocked down, they can’t get up again. All this issue we’re having with the the sudden death myocarditis situations that are out there – we were worried about that kind of stuff. So the mitochondrial function is critical to look at that, to make sure that’s working, and then there’s certain mitochondrial supplements that you can try that will help there. Peroxisomal function.

We just talked muscle mass, right. The biggest issue at the end is fasting triglycerides, right? It’s a simple little. 10 cent test I guess, but it’s critical – just because these are old tests doesn’t mean they’re not valuable. Sometimes these old tests are really the most valuable.

00:48:05 Julie

I love that you included some of the basics in the ProdromeScan. It has all these high level metabolomics and then you have some basics.

00:48:11 Dayan

Right. Because ohh, you would think, I have to get this super fancy test. But I went well, no, you don’t really need the fancy one.

00:48:20 Julie

Right.

00:48:21 Dayan

You need to get the core thing, and that’s really peroxisomal function, cholesterol regulation and transport, which is obviously very important for the ApoE4 community, and then sarcopenia type markers like creatinine and then your NAD type with uric acid – make sure that those molecules are in place … C reactive protein for inflammatory.

And there’ll be some other ones that you guys are now involved in. We’ll have other markers that will be available. We have to depend upon the the shipping requirements, but there’s a whole new suite of additional markers that will be available, and of course your blood samples are always biobanked, so we can do other things in the future.

00:49:01 Julie

Well that is wonderful. And I think just to kind of summarize, the ProdromeScan lets you assess your cellular health before symptoms show up. And that’s why your scan is so perfect for our community, because as you know, ApoE4 is not deterministic. We’re at risk for dementia and heart disease. And we want to know if things are moving in the wrong direction before things start to go wrong, and that’s where we think partnering with you is just amazing.

00:49:34 Dayan

The ProdromeScan test is designed to ask the question, why? Not what. It’s not about, what is your marker? It is, why is your biomarker the way it is? Because when you look at your blood work, that is a representation of … your body has chosen that as its best situation in your environment. So it’s the other way around. You have to question why is my homocysteine at 12? OK, it’s the “why” question. Cause the blood test is your body communicating to you – now you have to ask why, and then once you understand the why, then you need to change the why by changing the environment of the body. And the biomarkers will change afterwards. The biomarkers are not driving your health. Your biomarkers are a marker of your health.

So we’re looking at your equilibrium. So you need to look behind the curtain.

00:50:22 Julie

Right.

00:50:22 Dayan

That’s what it’s there for, is to say, OK. And then now you can now you can start interactively …

00:50:29 Julie

I love that and yeah, so we’re hoping that we’re going to get lots of people participating, repeating the ProdromeScan every six months or whenever it makes sense, and we’ve created a software platform where we can anonymously share this information with other members of the community. In addition to the ProdromeScan, we’re gonna collect the basics like their age and their height and their weight and their blood pressure. And some other basic biomarkers, if they want to share it, but also what their current diet looks like, what their exercise regimen looks like so that we can track … and their cognitive status – I should have said that – that’s most important. So that we can track people, we hope over a period of years. And we can see ApoE4 carriers that are doing better and we can ask the question, why? And we want to be able to look under the hood and this will be an open access dataset. So we’ll invite everyone to study us. Whoever wants to.

And we’re going to kick this off with a webinar, and you very graciously agreed to join us for that. And at that webinar you’ll be looking at pre and post ProdromeScan of two volunteers. And we’ve decided to use two different interventions for this initial kickoff webinar. And we’re currently looking for volunteers who are not fasting right now and who are not doing strength training. And so, if you’re an ApoE4 carrier and you wanna volunteer, please send an e-mail to [email protected], and you can volunteer for the project or you can learn more about it. And we should be kicking everything off in about 3 months and we hope you’ll join us for that.

And before we say goodbye, I just wanted to ask you, how can listeners learn more about your clinic, your rehab and recovery program?

00:52:30 Dayan

So basically if you go to drgoodenowe.com, that’s where all the educational content is. There’s a page on the clinic there and there’s an e-mail link to ask for more information and see if you qualify for the program. And so that’s all available on drgoodenowe.com.

00:52:49 Julie

Ohh, fabulous! And I wanted to ask if there’s anything else we didn’t cover that you want to share with the community.

00:52:57 Dayan

Oh, there’s always 1000 things that we’re doing, but no, I think the biggest thing with ApoE4 is a cholesterol regulation situation that the book goes in great detail on the ApoE4 genotype and how the SNP actually … what it does.

And it’s not something people should be afraid of. The goal of all this stuff that we’re talking about is not to create an obsessive watching of your health. You should be able to find a pattern and a lifestyle that you say, OK, this is working for me, and then you shouldn’t have to be obsessing on it every month of your life.

00:53:32 Julie

I completely agree.

00:53:34 Dayan

And check on it every now and then.

00:53:34 Julie

I feel like I’m leading a joyful life, and I appreciate the awareness that I’m an ApoE4 homozygote. The book you’re referring to is Breaking Alzheimer’s. I think it’s available on Amazon. And at drgoodenowe.com, I would imagine. OK, and I highly recommend that.

And before we say goodbye, I just want to say what a huge achievement this is. We are now reaching the era of treatable dementia. Your clinic is doing this. Are you familiar with Doctor Heather Sanderson?

00:54:10 Dayan

Yes, I’ve met her.

00:54:14 Julie

Yeah, so she’s got her clinic in California. She’s opening one in Kansas. And people with dementia are going to the senior care treatment center and they’re going home. So that is such amazing news for ApoE4 carriers. So, so grateful for your work that you’re making this possible and grateful for sharing your time with us today.

00:54:37 Dayan

Well, thank you, Julie. I’m looking forward to working with you.

00:54:39 Julie

Alright, alright, thank you so much, Dayan.

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Dr. Hussein Yassine joins Julie Gregory to discuss the work his lab at the University of Southern California has been doing to understand brain biochemistry with special emphasis on interactions with APOE genotype.

00:00:25 Julie

Hi friends, I’m very excited to have Dr. Hussein Yassine, an associate professor at the University of Southern California, as our guest today. The Yassine lab works on understanding how changes in brain lipid metabolism predispose individuals to develop Alzheimer’s disease pathology.

Dr. Yassine is an expert in brain lipid metabolism. The Yassine lab approach combines imaging studies, clinical trials, observational cohorts, and animal models with a focus on Alzheimer’s disease as it relates to APOE and is actively funded by the National Institute of Health.

Dr. Yassine is the leader of the research and education core of the University of Southern California, Alzheimer’s Disease Research Center. He’s also the current co-chair of the Nutrition, Metabolism, and Dementia professional interest area of the Alzheimer’s Association.

The Yassine lab has uncovered important structural and functional changes and lipoproteins from both cerebral spinal fluid and plasma of patients at risk of Alzheimer’s disease based on the ApoE4 genotype. Dr. Yassine is the principal investigator of Prevent E4, a randomized clinical trial testing whether high dose omega-3 supplements can slow down cognitive decline in ApoE4 carriers, when started before the onset of clinical disease.

Dr. Yassine’s basic science lab investigates mechanisms of ApoE4-associated brain pathology focusing on APOE / ABCA1 interactions, brain inflammation, and develops biomarkers and drugs based on APOE and brain lipoproteins metabolism.

Welcome Dr. Yassine. Thank you so much for joining us. I was really looking forward to our discussion today. In order to prepare for it, I was listening to your previous interview with Dr. Peter Attia that was really an epic discussion. I’d like to start by learning more about you. Tell me a little bit more about your background and how you became interested in studying ApoE4.

00:03:04 Hussein

Right, so my background is I I got training into endocrinology specifically within endocrinology, lipids,  and then within my niche of lipid specialties I was studying lipoproteins in the blood. And we were interested on the function of HDL particles, otherwise known as good cholesterol. We stumbled across important roles for APOE in the blood, and at that time I moved from Tucson to Los Angeles to join USC, and USC had a very strong Alzheimer’s program. The chair of Neurology at USC came to me – Helena Chui – and she said, “Well, do you know that APOE has a major role in Alzheimer’s disease?” – and we’re talking 2012 now – and I said, “Well, yeah, I’ve heard about it; it seems to have many roles.” And she said, “Would you be interested in getting some small funding to look at what APOE is doing in the brain?” And I said, “Why not?” And it was a slippery slope from that time until now, almost a decade.

And my lab has focused on APOE since in the brain and trying to understand what it does, how it works, and if there’s anything we could do to prevent or change the course of ApoE4 on an aging brain.

00:04:35 Julie

Well, interesting, my interest in ApoE4 began at the same time because in 2012 is when I learned I carried 2 copies of the gene, and back then, as you know, much, much less was known, and in terms of clinical advice given to patients there was very little information. At that time, we were told to eat a very low fat diet, and we were told to do crossword puzzles and square dancing. And I thought, really? That’s what the medical community has to offer us.

So things have evolved, thank goodness. And thank you for your interest in this gene. We we need more people like you.

I’m going to start with a really monster question, but we’re going to break it down into bite sized pieces. What do you perceive to be the top three mechanisms by which ApoE4 leads to dementia and or cardiovascular disease? And then I’ve got little follow-ups for each of those mechanisms. So if you want to go one by one, we can do it like that. Or you can share all three at the top. Whatever you prefer.

00:05:50 Hussein

So these are great questions, and I don’t claim to have the answer to those questions. All what we have is some bits and pieces of this puzzle, and we’re trying to piece it together. So I think more and more research is coming. And proving to us that we have to be humble.

00:06:06 Julie

Oh, I totally appreciate that. And I share your humility. I am learning more every single day.

00:06:14 Hussein

Right, so let’s maybe start by asking what APOE is and then possibly get to the answer right after.

So APOE as you probably know is a gene. And encodes its APOE protein. Now our interest in APOE is because in nature APOE is found three in common variants with three forms, what we call E2, E3, and E4. E3 is by far the most common – approximately 70% of people have the variant. Less so would be E4 – 20 to 25% and that can actually vary by ethnicity as well. So whites and Africans may have different population frequency. The common example is in Nigeria, up to 50% of the people are E4 carriers. E2 is less common. Approximately anywhere from 5 to 20% depending on the population. E2 is protective against Alzheimer’s and in fact is one of those very few genes that has been shown to be associated with a longer lifespan. E3 is neutral, and E4 increases the risk of Alzheimer’s. One copy slightly increases the risk of Alzheimer’s and two copies significantly increase the risk of Alzheimer’s. That is what APOE gene and protein exist. These are the forms that they exist.

Part of my interest in this APOE is because it makes HDL particles, meaning that it can get lipidated. It carries lipids like fats and cholesterol and becomes a truck carrying those fatty molecules both in the blood and in the brain, and are the most common mechanism for people to attribute or are interested in APOE is by their lipid carrying capacity. So the initial view of APOE mechanism as an AD or Alzheimer’s disease risk factor was tied to its ability to carry lipids between different cell types in the brain. For example, between the helper cells known as astrocytes and the neurons, which are the main brain cells responsible for our ability to a have a cognition or to fire to make memories.

So that’s the first impression of how it works, but as we learn more and more about APOE, more things have evolved and more important now than carrying lipids is the ability of APOE to regulate inflammation. And those two mechanisms are not separated from each other, meaning that the ability to carry and exchange lipids is associated with the ability of cells to become more inflammatory or less inflammatory, and those two mechanisms are coupled. And now most people, some people at least, believe that this inflammatory process in the brain could be playing a big factor in the evolution or development of diseases like Alzheimer’s dementia.

There are other mechanisms that have been attributed to ApoE4 that are related to both lipids and inflammation, and they include blood vessels changing their behavior, becoming leaky, or having atherosclerosis or stiffening up because of lipid accumulation. Other mechanisms also include the response to trauma, the ability of the brain to respond to trauma, whether it’s injury falling, epilepsy or any of that. E4 carriers tend to respond by being more inflammatory and producing more disease in response to trauma.

So I would say yeah, the ability to exchange lipids and the ability to modulate inflammation would make the ApoE4 brain more prone to getting disease, and maybe finally ApoE4 as a third mechanism – if you’re looking for three – it has ways that it interferes with the metabolism of nutrients, including fat and carbohydrates and that could possibly also put the aging brain at increased risk of neurodegenerative diseases.

00:11:01 Julie

OK, I love all three of those mechanisms. They’re really, really good. Let’s start with the first one. The exchange of lipids and how ApoE4 carries lipids differently than the other APOE genotypes. Help us better understand that.

00:11:19 Hussein

Yes, so lipids are not soluble in water. The classic example like it is you’ve got this meal. You decided to use your pan, then you started to cook and you had great greasy meal full of fat and then you want to clean the pan after frying the meat for example, you turn on the water faucet, but you’ve realized that the water is not able to efficiently extract the fat sticking to it because water and fat are not mixing.

So what do we do to solve this problem? We add some soap right? So APOE is behaving like soap. So what APOE does it takes the fat and the water and allows them to form particles or missiles or lipid droplets. And then they can dissolve and become entities which can circle it. So fat he will not get suspended, it just cannot. It will crash out of the solution. The blood solution.

So to be able to get transported whether it’s going to be in the blood or across the cells in the brain, it requires to be packaged in droplets, and APOE is efficient in doing that. And that’s my principle that APOE does the packaging of fat and its distribution between different samples.

00:12:46 Julie

Interesting, so let’s talk about how ApoE4 does that perhaps less well than ApoE2.

00:12:55 Hussein

Right, so I would not say less well or worse or better because it differs by ethnicity. It differs by, so I would argue that in Africans who are ApoE4 probably descended from a tree of lineage in Africa and then we started exchanging genes ApoE4 is very functional and not associated with Alzheimer’s.

The mismatch happens because we live in an environment now that is more sterile, less infections, and we were able to get to 80, 90, 100. But if we did not age and we were living in rural areas where our exposure is to parasitic infections, other infections is prevalent. In fact, if you were an E4 carrier, you will have a survival advantage.

So we would have to look at ApoE4 as a mismatch as opposed to being less efficient but more efficient. It’s quite an efficient system. In fact, our ancestors, based on genetic studies of the past, suggested that all of them had E4 and was time you started getting E3s and E2s. So in that regard, I wouldn’t call ApoE4 good or bad. It’s just a mismatch. So the mismatch happens when E4 carries lipids differently than E3 or E2. E4 tends to carry less lipids than E3 and E2 and because of that amino acid substitution that makes E4 E4, it tends to aggregate, meaning that the ApoE4 particle tends to clump and carry less lipids.

Now, why is that the problem? Well, it might be a problem because the ApoE4 system, when it clumps, can induce a greater inflammatory response. And in populations exposed to infections that greater inflammatory response would clear the infection and will assist the body in getting getting rid of sepsis in case a pregnant woman is getting septic, unfortunately, because of her exposures to infection and that term in pregnancy is known as puerperal sepsis. An E4 female can effectively fight puerperal sepsis and deliver infants compared to an E2 or an E3 female. And an E4 carrier living in rural Ghana or in the Brazilian slums is more efficiently fighting parasitic infections than others.

Now we move now to northern latitudes and let’s specifically talk about Northern Europe where ApoE4 is predominantly transmitted to whites, and they’re living in environments where there isn’t really much infections. The inflammatory response that ApoE4 is supposed to be fighting infections is now misdirected and it is leading to a sterile inflammation that manifests in the accumulation of amyloid in the brain or some form of atherosclerosis and blood vessels outside the brain. So here are examples where we see the mismatch between ApoE4 in different ethnicities depending on the environment that exists.

00:16:29 Julie

Right, we actually know of several primitive hunter gatherer tribes like the Tsimane in Bolivia, and certain groups in Nigeria that are ApoE4 carriers, and they do extraordinarily well and because of everything that you just described.

I kind of want to get back to a APOE to better understand that mechanism though. So my understanding is that ApoE2 carriers have higher levels of peripheral APOE compared to ApoE3 carriers and ApoE4 carriers. Does that play a part in this mechanism? Is MORE better?

00:17:14 Hussein

Not necessarily. Part of the response or part of what APOE does can be assessed by the levels of APOE. But the reason why I’m a little ambivalent and not strong about the answer is because that doesn’t translate into the levels of APOE in the brain. In the brain, E2, E3, and E4 levels are not different as much as they are in plasma, and that has to do with the clearance and how APOE is cleared from the blood. ApoE2 is cleared at a much slower rate in the liver compared to E3 and E4, but in the brain the clearance pathway is different. And changes in the levels of APOE in the blood may not translate to changes in the level in the brain because these are two different compartments. APOE in the blood is made in the liver to a large extent, less extent is made in macrophages and other cell types, but in the brain the large production site for APOE is going to be your astrocyte and to lower extent your microglia or immune cell [inaudible] parasites and other subtypes.

So these are two different pools of APOE and their levels may actually differ based on whether they’re in the blood or in the brain. So yes, you’re correct in that ApoE2 has greater levels in the blood, but that doesn’t translate to changes in the brain.

And increasing ApoE2 in the blood may or may not result in changes in APOE levels in the brain. This is a good area of study, and more research is needed to understand this crosstalk between the brain and the blood.

00:18:56 Julie

Right, are you familiar with research done by Katrine Rasmussen from Denmark?

00:19:04 Hussein

I have seen some of that, but … you have a specific …?

00:19:08 Julie

Well yeah, so she took a very large data set. I want to say over 70,000 people over a very long period of time for a clinical trial. I think it was over seven years, and she looked at peripheral levels of APOE and she found a very strong correlation. Those that had low peripheral levels of APOE, regardless of APOE genotype, tended to develop dementia as they aged. So people that had higher levels of APOE appeared to be protected, and that kind of follows the APOE 2/3/4 story.

So you know, I know that we don’t know how that translates to APOE in the brain, but it makes me wonder if that’s a biomarker worth tracking. I think she’s written a few papers about it.

00:20:05 Hussein

Yes, I’ve heard that story and I can tell you it’s an interesting concept that needs to be tested. Now, here’s what we don’t know. What we don’t know is: does lower levels of equally in the blood mean means that there is something in the brain that’s also happening at the same time that is making the risk of Alzheimer’s bigger and the higher levels of APOE in the blood also means the same process that’s leading to higher levels of it in the blood is causing APOE in the brain to function better. So we don’t know whether that same reason why you have higher APOE levels in the blood or lower APOE levels in the blood is causing something else in the brain that leads to less or more dementia.

00:20:53 Julie

You’re right, it’s just a correlation now. We don’t understand the connection right?

00:20:57 Hussein

That’s why we have to be careful in moving to the next step and assuming that higher levels of APOE in the blood means we should give people APOE. We know that when you increase the levels of APOE too much in the blood, you can get very high triglyceride levels.

00:21:18 Julie

I noticed that. So it actually predisposes you to cardiovascular disease. So it seems like there’s a fine line. It’s a balance, yeah?

00:21:26 Hussein

It can’t be too little or too much just right.

00:21:32 Julie

Right, oh boy, you know I kind of want to go back to the mismatch theory. So if you were me, an ApoE4 homozygote of European ancestry, should I get some parasitic infections and play in the mud?

00:21:51 Hussein

Should your children be exposed to more infectious environments, and I I would argue that it may not be a bad idea. We need to develop, we need to tune down our immune responses and we know in conditions like asthma we might talk a little bit about the autoimmune nature of Alzheimer’s.

In conditions of asthma, communities that are exposed to hay and other allergenic responses at a very young age are protected from asthma than communities who live instead in sterile environments.

00:22:23 Julie

Interesting, yeah, and it’s same with children that are exposed to pets. They are healthier, right?

00:22:30 Hussein

Yes, exactly.

00:22:31 Julie

So there certainly is something to that for sure. Let’s move on to inflammation. Come talk to us about how that mechanism works as far as it relates to ApoE4.

00:22:47 Hussein

Right, so inflammation is a very difficult area of research to study because it’s it’s not as simple as we think it is. The definition of inflammation varies from one setting to another. There’s an inflammation that happens after you get an acute infection. There is an inflammation that happens with chronic conditions like cardiovascular disease and Alzheimer’s, and they may not be the same thing. What we know is that inflammation is a way for the body to adapt to injury so when there’s a chemical injury or a construction agent or a traumatic injury, the body responds by creating first an acute inflammatory response where the immune cells try to circle the agent or the injury side and then slowly that inflammation resolves and the inflammation goes away.

The problem with ApoE4 is that it associates with … when the inflammation happens, associates with poor resolution, so instead of resolving quickly it lingers and stays for a long time and that lingering, unresolved inflammation now becomes the problem.

There is no evidence that ApoE4 by itself creates inflammation. In fact, the more we learn about ApoE4, the more we understand that ApoE4 mishandles inflammation. When you look at all ApoE4 carriers, you would find a lot of ApoE4 carriers with no inflammation. Where is this cross talk or interaction? This interaction happens when an ApoE4 carrier has inflammation. The risk of disease gets higher.

00:24:43 Julie

And that’s actually been shown in one study that was pretty poorly designed regarding COVID-19 in ApoE4 carriers. I don’t know if you saw that, but we had poorer outcomes, and I say it was poorly designed because I think the data set was all people who were in the hospital, so we have to assume that there were many ApoE4 carriers who got sick and stayed at home and did fairly well.

So it makes me wonder, as an ApoE4 carrier, what inflammatory biomarkers should I be tracking to make sure I don’t have inflammation in my body?

00:25:09 Hussein

We don’t really have the answer to that, but we may have tools.

00:25:26 Julie

OK.

00:25:27 Hussein

So in the Framingham cohort north of Boston they looked at the C Reactive Protein as a measure of blood inflammation, and they found out that E4 carriers had possibly less levels of C Reactive Protein, less inflammation.

But that’s not the story. The story in ApoE4 carriers who had higher C Reactive Protein for some other reason, they decline and progress to have Alzheimer’s disease at much faster rate than those E4 carriers without high C Reactive Protein. So the nuance is that ApoE4 is not causing the high C Reactive Protein because more ApoE4 carriers have lower C Reactive Protein, but those unlucky ApoE4 carriers who for some reason have chronic inflammation, whether it’s diabetes, cardiovascular disease, some form of response that the body is now turning to an inflammatory state, they do not do well.

00:26:41 Julie

Wow. So there aren’t other specific inflammatory biomarkers that you would track like TNF Alpha or any of those – IL-6?

00:26:52 Hussein

IL-6 and TNF Alpha are produced by the same mechanism in the liver that leads to … in fact, IL-6 gets converted to C Reactive Protein so they have [inaudible].

00:27:00 Julie

OK, so in our community lots of people tracked our C Reactive Protein, and many of us try to keep it below 1. And as you noted, and as the Framingham study showed, that seems to be pretty easy for many of us. But occasionally I do see members of our community that have really high numbers kind of inexplicably, and so that’s probably an indication that something else is going on.

00:27:28 Hussein

Right, and ApoE4 does not know how to respond to inflammation, and that’s why it gets into trouble.

00:27:34 Julie

Right, and we would basically treat that by tracking down whatever the root cause is. If it’s obesity and metabolic syndrome, we would address that and … or whatever, I would imagine.

I kind of want to go backwards ’cause I should have asked you this before. So, we know that ApoE4 carries lipids poorly. Are there any biomarkers surrounding lipids that you would pay particular attention to if you’re an ApoE4 carrier?

00:28:09 Hussein

The answer to that is yes. We know that ApoE4 carriers, not all of them, a portion of them inefficiently carry cholesterol, and when I say inefficient, I mean that the ApoE4 protein goes to the liver and sticks to the LDL receptor. And when it does that it forces the LDL receptor to function less. And the LDL receptor has an essential mechanism in clearing cholesterol from the blood. So some ApoE4 carriers may have higher levels of LDL cholesterol, and that can tell you that the ApoE4 system is not efficiently able to clear or get rid of cholesterol. And it’s another indication of how this ApoE4 is not efficiently allowing the metabolism [inaudible].

00:28:59 Julie

Right, so many of us track our standard cholesterol panels, but we also do the advanced panels to see what those lipids look like as well. And certainly I’d say we have a pretty high percentage of people in our community that do end up having high LDL cholesterol. But sometimes not a high LDL particle number, which makes it less concerning, especially if oxidized LDL is low.

I love your focus on HDL. My understanding of the research, and I know nothing is conclusive, seems to be that a higher HDL would be protective for ApoE4 carriers. What do you think?

00:29:47 Hussein

Let’s take a step backward and talk HDL first. HDL is a particle that carries lipids, including cholesterol. HDL cholesterol is not the same as HDL particles. You could have higher HDL cholesterol with not more number of HDL particles; you could have lower HDL cholesterol and a lot of HDL particles. The other example is you can have a lot of buses with no people riding them, and you could have a lot of buses with tons of people riding them. And the cholesterol here is the rider of the bus.

So a large number of HDL cholesterol does not necessarily mean that the traffic of cholesterol is faster or slower. Sometimes when you have disease states that block the exchange or transport of cholesterol, you can have an artificially high HDL cholesterol that’s not protective. And sometimes the high HDL cholesterol is a measure of a lot of traffic going to deliver for this excretion.

So I realize that doesn’t fully quench your thirst about, is high HDL cholesterol good or bad? And I think my answer to that – it depends on the context. And somebody who is exercising, good genes – their parents lived to 100 – a high HDL cholesterol reflects the status of active flux of cholesterol from tissues to the liver for excretion. But in somebody who has, for example, type I diabetes, drinks alcohol, and has other problems, the high HDL cholesterol reflects a dysfunctional state

And low HDL cholesterol also holds the same concept. You could have low HDL cholesterol. And be in a disease state, and you could have low HDL cholesterol, but your HDL flux is high and you could be functional, so that’s why I would argue for people not to put so much money on what the HDL cholesterol level is, because that has to be interpreted with caution.

00:31:49 Julie

It has to be interpreted with the whole clinical picture in mind. I certainly appreciate that. How about the HDL particle number? Would you say a higher particle number or lower particle number would be more protective for ApoE4.

00:32:07 Hussein

We don’t know that. I think it’s a great question, and I think we need to study that in more detail. And my lab is certainly interested in this question, and we’re measuring HDL particles in people with and without ApoE4 carriers. We’re not really finding a big hooray answer, but what we will hopefully publish soon – it’s in review right now – is if lowered HDL particle numbers in the brain associates with features of Alzheimer’s disease?

00:32:35 Julie

OK, and are lower HDL particle numbers in the periphery correlated with lower HDL particles in the brain?

00:32:44 Hussein

It did, but it was not as strongly associated with what’s happening in the brain compared to HDL particles in the blood.

00:32:52 Julie

OK, so HDL, of all the lipoproteins, is there any crosstalk between the periphery and the central nervous system with HDL?

00:33:05 Hussein

We just published a review on this last month. So the dogma says there is no [inaudible] because these are two different components. But we’re finding in our studies that the small HDL particles, because HDL exists in many different sizes, we’re finding that the small HDL particles are correlating between blood and CSF, which is a measure of brain HDL for cerebral spinal fluid, and we’re hypothesizing that those small particles might be exchanged.

00:33:36 Julie

Right, I think I’ve read some hints about that in the literature before, and I wondered if the small particles were able to cross the blood brain barrier. So that’s a paper that you’ll be publishing soon it sounds like.

00:33:50 Hussein

I’m hoping – it’s in review it now in Alzheimer’s and Dementia. We would find out in the next two to three months what the fate of that paper is, but we’re hoping that the scientific audience will appreciate this one.

00:34:04 Julie

Oh, I’m sure that they will. That’s something that our communities paid a lot of attention to – HDL.

So let’s move on to that third mechanism. You mentioned that ApoE4 carriers metabolize nutrients differently. Fats and carbohydrates. Can you expand on that mechanism?

00:34:28 Hussein

Sure, so this is where also my lab works on understanding.

One of the features of ApoE4 and its ability to modulate metabolism associates with changes in how mitochondria may be peroxisomes, and these are subcellular organelles that metabolize fatty acids. It affects how these areas in the liver possibly, and in the brain too, oxidize and metabolize fatty acids, specifically polyunsaturated fatty acids. So our study suggests that ApoE4 carriers tend to oxidize or break down polyunsaturated fatty acids at a higher rate than non-E4 carriers. In this process, it’s more pronounced with aging and as disease state ensues.

So what we specifically find, if we give an ApoE4 carrier and omega-3 rich diet, they tend to have less increases in their blood and the brain as measured by CSF compared to non-E4 carriers, meaning that the ApoE4 system is consuming more omega 3s than ApoE3 and E2. And that also to us means that ApoE4 carriers not consuming enough omega 3s is at a higher risk of omega 3 deficiency.

So we proposed a few years back, in 2017, 2016 that the ApoE4 brain could be hungry for omega 3s and would require a higher intake of omega 3s compared to the non-ApoE4 brain decades before the onset of disease.

And we also propose that as a disease ensues, the brain switches through a system that hyper oxidizes or increases the catabolism or destruction of omega 3s, that it becomes futile to start these supplementations after disease ensues because it’s no longer using them in the right direction.

So what we mentioned in the 2017 paper in JAMA Neurology is that we think E4 carriers, decades, decades we were talking from 20s to 60s consume more omega 3s because the ApoE4 brain is hungry for those. But once you develop the disease status, it may not make a difference because you switch now into a different metabolism state where omega 3s can no longer be protective.

That’s one aspect that my lab is doing, and in fact we got funded by both NIH and the Alzheimer’s Drug Discovery Foundation to launch a relatively large trial. We call it Prevent Before where we’re giving ApoE4 carriers relatively higher doses of omega 3 supplements over two years. But we struggle to find those E4 carriers because 1) you have to be ApoE4; 2) you have to not like eating fish because we’re looking for people who do not consume omega 3s; and 3) you cannot have dementia or cognitive impairment, so we’re looking for people between the age of 55 and 80 who happen to carry an E4, not eat a lot of fish and don’t have disease. And the reason why we’re looking in this age range is because if you look at younger people, you won’t find changes in cognition. So we wouldn’t know if it’s going to be working well. So we want to catch them a year or two before they have disease to see whether the supplementations with large doses of omega 3s can alter or or make a dent in the progression towards disease.

So that’s one aspect of the answer to your question. There’s another aspect.

00:38:22 Julie

Yeah, OK, let me ask a quick question. So you say high dose of omega 3. What is the dose that you’re giving people in the trial?

00:38:33 Hussein

We’re giving them two grams per day of DHA.

00:38:36 Julie

DHA. OK and what type of DHA?

00:38:41 Hussein

It’s produced in algae and it’s vegan and it is what’s known as triglyceride based DHA.

00:38:43 Julie

OK, and why did you choose to do a vegan based DHA?

00:38:56 Hussein

I didn’t specifically choose to do a vegan based, but this form of DHA has been studied extensively before, it’s available, and we know that this form of DHA efficiently raises the amount of DHA in the blood.

00:39:03 Julie

Got it. So I know that we need to move on to part two of your answer to this question, but I sort of want to stay here for just a moment. So if you were an ApoE4 carrier like me, I’m 59 years old and not showing symptoms at the moment, it would be a reasonable suggestion that I would not want to skimp on my omega-3 fatty acids at this part of my lifespan. I would imagine.

00:39:43 Hussein

Let me also reflect humbleness because we don’t know, and I do not want to give you information that’s not supported by strong evidence because if we had evidence this should be a recommendation, not a trial. We wouldn’t put E4 carriers on placebo.

But to answer your questions, I think if I were an ApoE4 carrier, I would possibly want to increase my omega 3 consumption from fish. And I think the reason why I’m focusing on fish because fatty fish contains so many other nutrients besides omega 3s that makes the body’s consumption of omega 3 much more efficient.

00:40:18 Julie

Right, absolutely. So let’s move on to Part 2 of how ApoE4 carriers metabolize nutrients differently.

00:40:36 Hussein

So the second part has to do with body weight and insulin resistance.

00:40:39 Julie

Can you repeat that?

00:40:44 Hussein

Insulin resistance. ApoE4 we know is associated with more insulin resistance and lower body fat. Typically ApoE4 carriers can be skinnier, but they are more insulin resistant, meaning that they don’t really know how to metabolize glucose.

So one of the things we are interested in studying is what is the effect of maybe modulating insulin resistance on the ApoE4 brain? And one way to alter insulin resistance is through exercise. One way to alter insulin resistance is through a low carb diet. One way to alter insulin resistance is through weight loss.

Now we don’t really fully understand what the recommendations should be like, but we have hypotheses, and please take this with a grain of salt, because it’s a hypothesis. We don’t think caloric restriction or losing weight is a good idea for ApoE4 carriers, despite the fact that it improves insulin resistance, based on basic science studies suggesting that ApoE4 adipocyte Is not able to tolerate weight changes graciously, so an ApoE4 carrier who loses more weight might be at higher risk of diseases than an ApoE4 carrier who maintains or even gains weight.

00:42:14 Julie

Wow, and overall that applies to everyone of every APOE genotype. It’s been a little surprising, but it seems like people that are of a slightly heavier weight seem to be protected somewhat.

00:42:31 Hussein

Yeah, I can’t tell you how it works by genotype because the studies have to be done and they’re not done yet.

But we have enough epidemiology observational [inaudible] suggests that older ApoE4 carriers with heavier weight do better than older ApoE4 carriers with [inaudible]. This is an association or a correlation. We don’t fully understand that, but we know that in mice models, when you feed a mouse to a diet that’s rich in elements that can make the mouse diabetic or insulin resistance, the ApoE4 mouse tends to gain less weight but become much more insulin resistant than the ApoE3 or ApoE2. Because they cannot expand their depots efficiently.

00:43:22 Julie

That is fascinating. So we also know that as ApoE4 carriers become insulin resistant, they’re less able to use glucose in the brain, and I guess imaging studies have shown that we have issues with that starting as early as age 20 if you’re going to look at the studies from Eric Reiman and Richard Caselli. And in the same regions of the brain as Alzheimer’s patients, even though these 20 year olds aren’t showing symptoms, they still have that deficit of being able to use glucose efficiently in the brain.

00:44:00 Hussein

I have to caution you that these findings don’t apply to heterozygotes. Those findings are largely driven by homozygotes and have not been reproduced yet. In fact, larger studies which have happened decades or maybe years after Eric Reiman published these findings didn’t reproduce his findings.

The majority if not all studies that came later do not show that younger ApoE4 carriers have deficits in brain glucose uptake.

00:44:31 Julie

Very encouraging.

00:44:32 Hussein

So when you look at large cohorts, hundreds of people, you realize that, for example, a study by Knopman from the Mayo Clinic suggested that the changes in glucose metabolism in the brain in ApoE4 carriers do not appear before the age of 60, and he studied approximately 800 individuals. And if you want to dig deeper into what Eric Reiman’s findings where 20s and 30s they might have been biased toward ApoE4 homozygotes in a very small subset of patients, so we don’t know whether it just happened by luck, that those ApoE4 carriers had more severe disease, but in general there is no evidence that younger ApoE4 carriers have strong deficits in brain glucose metabolism at this age. It appears to happen at older age and perhaps five years before non-carriers.

00:45:34 Julie

Right, that’s very encouraging, and I think you’re right, Dr. Reiman’s data set was certainly rich in ApoE4 carriers, and it was certainly people at very high risk and probably more homozygotes than heterozygotes, but so that would make sense. And I also wondered about the metabolic health of that data set because that finding was so surprising.

00:46:01 Hussein

Yes, and you know, since that publication we’ve had many papers that do not show a clear signal that ApoE4 is doing that to the brain at that age. Now, ApoE4 may have a lot of effects on the brain, and it is possible that in some ApoE4 homozygotes you could clearly see some signal, but in general it’s diluted out.

In fact, we have published the paper in 35 year old ApoE4 carriers showing increased omega-3 brain uptake. And what we and again, it’s a small subset, 35 individuals. We still have to reproduce it in a larger group, but what that suggested to us is that the ApoE4 brain is consuming more omega 3s than the non ApoE4 brain, possibly because it prefers fat over glucose.

00:46:54 Julie

Right, and many people in our community and we know we don’t have definitive research, but many of us are using a low carb approach and very regular exercise. And you know, certainly trying to make sure we have enough omega 3s on board so everything you’re saying beautifully dovetails with what people in our community are doing.

I guess that brings me to my next question. If you were an ApoE4 carrier – and I don’t know that you’re not – but what diet or lifestyle strategies would you be using to protect yourself from the effects of ApoE4?

00:47:38 Hussein

Right, it’s a great question. Let me start by saying we need to do more research into it, and I think the ApoE4 community should stand up and work together to support more ApoE4 research. We’ve had decades of research into amyloid and tau, but we’ve only started to scratch the surface of ApoE4. And we know that ApoE4 is by far the strongest genetic risk factor for late onset Alzheimer’s disease. So that’s why fundamentally if there’s anything that the community can help with, it is to spread the word, support ApoE4.

Coming back to your question is, if I knew that I was an ApoE4 carrier, what can I do to change my life span risk of having dementia or cognitive diseases with age?

One I would probably consume more fat than carbohydrates, and when I talk about fat, I’m more referring to healthy fats and not saturated. That includes nuts; that includes fatty fish, avocados, and olive oil and so forth.

I would consume less simple sugars. Simple sugars come in the form of sodas, cakes. Because we know there’s an association of simple sugars with diabetes at this moment.

I would definitely not smoke because we know that smoking would worsen vascular biology and make it higher likelihood that there’s vascular dysfunction in the ApoE4 system.

I would develop an exercise strategy where I would engage in at least 150 minutes in a given week. That’s 30 minutes a day, five days a week with some form of exercise. Doesn’t have to be high intensity. Could be as simple as an aerobic exercise where I stretch myself, walking fast, running, swimming – any form of exercise is good.

I would engage in some form of meditation that would clean up my thought processes and help me to reorganize.

Music and anything that can possibly de-stress and not cause any increase in stress.

Importantly, I would take any chronic disease in middle age seriously. So if I had diabetes, hypertension; if I had, you know low vitamin B’s. If I had anything that could possibly put my brain at risk, I would deal with it when I’m asymptomatic. Between the ages of 20 and 60, not wait until after 60.

There are other things that we haven’t talked about, which is the importance of vitamin B for brain health. I’m not advocating for supplements. But what I’m trying to say is that the vitamin B has an important role in the transport of omega 3s to the brain. Vitamin B can be found in fish, could be found in green leafy vegetables, and other sources.

00:50:40 Julie

And I want to make sure I understand what you’re saying. Vitamin B.

00:50:43 Hussein

Yes.

00:50:44 Julie

B, as in a baby book, OK, and there’s so many forms of vitamin B, so which are you referring to – vitamin B12?

00:50:55 Hussein

B12 and B6 and folic acid.

00:50:57 Julie

And folate, right absolutely. And you know, a lot of people in our community pay attention to those three to keep homocysteine down.

00:51:05 Hussein

Yes exactly. So we want to do that because also we understand that the omega-3s to be able to get to the brain, they have to be on phospholipids and that reaction requires folic acid and B12.

These things go together and that’s why fish is a more complete source of omega 3s than supplements because the actual fish itself will have vitamin D, vitamin B, vitamin E, which is an antioxidant, lutein, which is an antioxidant. So that’s why sometimes just taking one supplement may not be sufficient.

00:51:43 Julie

Absolutely, it’s always best to get nutrients from food, as opposed to a supplement.

My final question for you is, do we know enough to do APOE testing? Should we be testing people?

00:52:00 Hussein

Yeah, I used to get asked that question a few years back, and then my answer was no. But my answer has evolved to yes, because we have a little bit more information than a decade ago.

And with the information we have today, I would tell the ApoE4 carrier exactly what we just talked about. If they knew that they were ApoE4 and they had a family history of dementia, they would have plenty of time to prepare and to do the best they can to avoid getting into later risks. You don’t want to certainly have this discussion at the age of 75.

00:52:37 Julie

Oh, absolutely. And you don’t want to learn later in life. It’s always better to know sooner. And I completely agree with you. We think everyone should know their APOE status. For instance, I wish I knew my son was an ApoE4 carrier before he decided to engage in extreme skateboarding and get a bunch of concussions on his head. I mean, so there’s lots of preventative things we could do.

I also would have paid so much more attention to omega 3s had I known when he was young. Although we are paying attention now. So yeah.

00:53:12 Hussein

Exactly. For the exact reasons that sometimes knowledge is bliss. In this case we are trying to make the argument that this should be part of a [inaudible] where when we see ApoE4 carriers we include genetic counseling, nutrition, exercise, lifestyle.

So it’s all good. To deal with ApoE4, we need a good understanding what it does, and that understanding will be influenced by many other things, including family history of dementia, including race, including age, including disease stage, the recommendation may differ for somebody who is 75 and someone who is 30.

So there’s a lot of research that needs to happen, but we’re starting to see the tip of the iceberg, and I think we’re heading in the right direction.

00:54:08 Julie

Oh, absolutely, and you shared a beautiful PDF with me that gave some advice, essentially for ApoE4 carriers. And you echoed it, much of it, in this discussion. But in our show notes, I plan to share that with our community if you don’t mind.

And I did have one question about that. I noticed that you recommend a lot of omega-3 rich foods that are plant sources, and you only recommend seafood like once a week. Why do you prefer the plant sources?

00:54:45 Hussein

I don’t prefer plant sources. It’s at least one time, one serving, so at least one, so you could have two or three or four. The evidence is really toward zero versus one is much bigger than one versus four.

00:55:02 Julie

Wow, OK.

00:55:03 Hussein

The people who do not consume any fish – the epidemiology evidence supports that they have greater risk of dementia compared to people who have one or two servings. But as you go from one or two servings to four, the risk reduction is not as steep.

00:55:18 Julie

Oh interesting, OK.

00:55:20 Hussein

I’m not saying that omega 3s is found in nuts is superior or inferior to omega 3s found in fish, although there is the argument that the human body may not efficiently make the fish derived omega 3s. From the plant-derived omega 3s, we cannot convert alpha linoleic acid, which is found in flaxseed or walnuts, to DHA and EPA.

But nevertheless, levels of alpha linoleic acid correlate with better outcomes. So people who consume nuts seem also to provide their brains with a nutrient that the brain likes.

Again, I’m not saying one is superior to the other. It appears that consumption of omega-3s – not binging on them – but just consumption at least seems to be protective for the brain.

00:56:14 Julie

OK, wonderful. Well I can’t thank you enough for sharing your expertise with us. If you would like, we’d love to help you recruit people for Prevent E4 if you’re still trying to get folks enrolled in the study, we can make an announcement on the site.

00:56:31 Hussein

Absolutely, so you can go to our website www.omega3brainstudy.com, and omega3brainstudy.com has the phone numbers, the protocol, the age group, inclusion / exclusion criteria, and you can support us by joining the study, spreading the word, talking to your friends, your family members.

This is an NIH funded study, which means it has been peer reviewed by people who are experts in the field. That also means that the budgets tends to be modest, so we wouldn’t have a big budget to fly people in, but we do the best we can to get them into the study with our resources.

I have to disclose that I have no conflict of interest for supplements – I don’t get paid by the supplement industry, and I’m not advocating for taking supplements. And if we knew that supplements worked, we would not do this trial.

The paper that you are going to upload on your website is not really an evidence based recommendation. It’s more of: we think this is where the science is today; this is the best available evidence we have today, but it might change; it does not guarantee that you do this and you don’t get disease; you may still get disease; it does not replace talking with your doctor.

But it’s the best available evidence we have today. And you know, if I made mistakes I will admit them. And if some of the recommendations need to be changed, they will be changed. We keep an open mind, and we realize that science is evolving. And new information will come in the future that makes this changeable.

00:58:09 Julie

Absolutely, and as I said earlier, we share your humility. We’re on this ApoE4 journey together and we’re learning more every day. And what I thought was helpful yesterday may not be the same as what’s helpful tomorrow, and so I’m always looking for new research. I’m looking to understand more and thank you once again for sharing your expertise. You’re very welcome to come back anytime you have new findings or want to share results of your clinical trial. And we will help you spread the word.

00:58:44 Hussein

Thank you so much, thank you.

00:58:44 Julie

Well alright thank you. Alright take care Hussein – bye bye.

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Dr. Sharon Hausman-Cohen joins Julie Gregory to discuss her company, IntellxxDNA, and her experiences using genomics intelligence to drive personalized patient treatment protocols. They discuss several ApoE4-positive patients for whom a comprehensive view was essential to overcoming health challenges and maintaining cognitive capacity.

00:00:23 Julie 

Hi friends, I’m very happy to be speaking with Dr. Sharon Hausman-Cohen today. She’s been using genomics for over a decade to deliver personalized medicine to help her patients achieve optimal health and wellness.  

As a researcher and clinician advocate, she recognized that information inaccuracies and complexity were barriers to entry for many trying to use genetic information. She saw the need for an easy to use, accurate science based genomics interpretation tool for clinicians and began to develop what is now IntellxxDNA. In addition to being a well respected doctor and researcher, Dr. Hausman-Cohen is a sought after speaker and educator on genomics, personalized medicine, and integrative medicine.  

Dr. Hausman Cohen received both her masters and medical degrees from Harvard Medical School. She’s board certified in family medicine and is a fellow of the American Board of Integrative and Holistic Medicine, possessing additional board certification in integrative medicine through the American Board of Physician Specialties. She’s been practicing full spectrum family medicine and integrative medicine for more than 20 years. She’s also the co-founder, chief science officer and medical director of IntellxxDNA that we’ll be talking about today.  

Welcome, Dr. Sharon! Tell me a little bit more about your personal background. What ultimately brought you from practicing family medicine to create IntellxxDNA?  

00:02:13 Sharon 

So in order to explain that, I think I’m going to go back one step before I went into medical school when I was in college. I was very involved in research and after college went to grad school, I was doing drug design making drugs more specific for the receptors. I did genetic research, and then I went to Harvard Medical School not to do a medical degree, but to do a PhD in medicine.  

And what happened is when I was there, I discovered that I was interested in too many things. I didn’t want to dedicate my life to just studying one pathway in the brain or one receptor. Really as a PhD you go deep deep deep into one topic, and I realized I like so many things that after I finished my masters I left Harvard Graduate School – it was a PhD program at the medical school – and then applied to the medical school, and because I liked everything, I chose family medicine because what is that but specializing in people birth to death? So that’s pretty broad. You get to learn everything, but then through my career I always was interested in evidence based medicine.  

I was always interested still in genetics and I was also interested in supplements and how they work because I had been an exchange student to Japan when I was younger.  

So over time I got involved in integrative and functional medicine and then people would be bringing me their 23andMe and saying, hey, can you tell me how to prevent heart disease, how to prevent Alzheimer’s? And when I would look at the different tools out there for clinicians for interpreting DNA there wasn’t one that was evidence science based for doctors and other healthcare professionals that not only told you what the different genes do, but how you can modulate them. And why would you order a test if you don’t know what to do with it?  

So for my patients I started setting out to kind of say OK, let me see if I can use your genomics to help you, and that led to the realization that every little SNP, the research of it, and figuring out how it works and how to modulate it took many, many, many dozens of hours, sometimes 100s of hours, and that I couldn’t do this just for myself. So my co-founder and I of the practice that we had – which was that we had moved to a practice that gave more private attention to patients – we said, let’s just build this tool. And so we did, and that became the groundwork for IntellxxDNA.  

00:04:51 Julie  

That is amazing. Having met you at one of Dr. Bredesen’s trainings, I know you are a dynamo and your interests are varied and you are so well versed on so many topics. At that particular training you were presenting on his Type 3, and I know that’s one of your areas of focus. 

You know, it seems to me that your product would be so helpful for people that are having complex chronic issues. Allopathic medicine works beautifully for acute things like pneumonia, but it’s you know so many people in our community are having these complex chronic issues, and it seems like your product would just work beautifully in those cases.  

00:05:38 Sharon 

It really does. I mean, I think that the way to think about it is … ApoE4 for example, which is obviously of great interest to your listeners. It’s one gene, but there are about 25,000, 30,000 genes in the genome, and ApoE4 interacts with, you know 1700 of them to start with, because it turns on and off a bunch of other ones, and so when somebody has an issue like an ApoE4 individual has a problem with mold or an ApoE4 gets long haul COVID, we’ve had the genomics really help us figure out how to get them well, because then we can kind of say oh this particular person some of their Achilles’ heels are, for example, that they make too much of a specific kind of inflammation, or that they really have more mitochondrial problems, so then we might give them more of those kinds of support … 

Whereas we had another guy and he’s an APOE 4/4 and he got really scared after he got COVID because his cognition just dropped. I mean we had him at, you know, essentially a perfect MOCA, really doing great. He’s only in his 50s, but he’s worried ’cause he’s APOE 4/4 and he does a lot to protect himself. And then his MOCA suddenly dropped down to like 22-23 and he was really, really stressed. As you can imagine because he uses his brain for a living. He’s in the world of finance, and that’s pretty important, and so we went into his genomics ’cause we have genomics on the vast majority of our patients, and he has something called Factor 5 Leiden, which makes you have thicker blood and make more fibrinogen. He also has other genes that relate to the brain not getting enough oxygen. So what we immediately did is we put him on lumbrokinase, which kind of helps with dissolving that extra fibrinogen. And we put him on a lot of pycnogenol. Because again COVID makes that fibrin that extra clotting problem worse.  

And then I saw him back literally 2 weeks later. And he’s like Doc, my brain is completely back to normal. Thank you so much. I was so scared and we wouldn’t have been able to kind of figure out what might have happened that quickly had I not known his genomics.  

00:07:55 Julie 

Wow, that’s a beautiful example of how your product could help members of our community.  

Before we dive into a couple of case studies, let’s take a step backwards and cover a few basics. What is genomics? What is a SNP? Can you kind of go over some of those things?  

00:08:14 Sharon 

Absolutely, and sometimes we’re so excited to talk about all these things that we forget that some people are listening that are new to this field.  

So a SNP sounds like it should be like a little piece of cloth, but it actually stands for single nucleotide polymorphism.  

And if you remember from science and for some people we didn’t get this until high school, kids are now learning this in 7th grade, but your DNA is that double helix and it’s made up of all these letters or base pairs, that we call nucleotides, and there’s only four. There’s A, G, T, and C, and it’s kind of like computer code with just 4 letters.  

You can do a lot by switching up the order and encoding for what your DNA makes, what proteins. Well if you switch out a letter in your DNA, so a single nucleotide polymorphism is switching out one letter, it might not do anything, but it might change from whether or not you’re going to have dark hair that’s curly or straight hair that’s blonde, and in the medical world, it might make it so that you make 10 times more of an inflammatory product like TNF alpha because it might be on the on switch or it may make it so that you don’t transport B12 well into your brain.  

So these little teeny changes can have significant changes on proteins, on hormones, on nutrient carriers. By themselves they don’t cause disease just like ApoE4 by itself is not causative for Alzheimer’s. Thank goodness. I mean 20% of the population has this, but it has an effect that can be modulated. 

So a SNP is a single change in the DNA that can have an effect. How big the effect is depends where that little change in the DNA is, so that’s that’s kind of that piece.  

Most genetic diseases are bigger events. There are some that are SNPs, but when you think of most genetic diseases there, they tend to be big deletions or big insertions, or sometimes it’s a SNP, but not the ones that we’re looking at, so our genomics looks at little changes in the DNA that by themselves don’t cause disease.  

But when you add them up with the interactions with the environment can have a profound effect in an additive way, so that’s the that.  

The other question you asked was what is genomics as opposed to genetics? Oh, I should have done that first, but genetics is kind of the study of heritability so there’s diseases that if your mom had, you have a 50% chance of getting, so that’s a genetic disease. But genomics is kind of more microscopic changes and so it’s genetic diseases again tend to be bigger events.  

00:11:01 Julie 

OK, as you can imagine epigenetics is huge in our community. As most in our community know, epigenetics is the study of how specific behaviors and environment can cause changes that affect the way your genes work. Does your product take epigenetics into account? 

00:11:24 Sharon 

Well, one of the things that makes our product unique is we only list genes that we know how they work and that we have potential ways of addressing them of modifications.  

And the vast majority of our modifications would be considered working on epigenetics, so the classic medical definition of epigenetics has to do with methylation. Methyl groups can turn off genes.  

But we also know that food and environment and different things you know, exercise, can also have effects on the genome, so that definition of epigenetics has been expanded and, absolutely, every single one of the SNPs we look at. We give three, four, five, sometimes seven or eight different potential interventions. And some of them might be supplements. Some might be vitamins. Some might be foods to eat. Some might be things like exercise.  

So there’s a gene BDNF, and I think a lot of your community have heard of BDNF. So BDNF is the growth factor. That’s kind of like fertilizer for the brain. And there are about 4% of the population that are really, really bad at converting Pro-BDNF. the kind of storage form, into the active form. Well, if you’re in that 4%, if you really, really exercise more intensely, you can bring your levels of BDNF almost to the norm. If you eat a higher butyrate diet. So a keto diet is a higher butyrate diet. If you take certain things like green coffee bean extract or other supplements. Milk thistle can affect BDNF.  

All these different things and so we use the epigenetics in that broader sense is to say, OK, our DNA is not our destiny. What can we do about each of these genes? 

And just so you know that the BDNF one, the reason I brought that up is, BDNF, even if you don’t have ApoE4, if you have a combination of three BDNF genes, it gives you 2.7 times the risk of Alzheimer’s, so it’s almost as much as an ApoE4, so it’s a really important gene, so knowing how to modify it is important.  

00:13:33 Julie 

Wow, so on top of fine tuning our protocols it seems as though your product will help us also better understand our risk.  

00:13:45 Sharon 

Absolutely! So one of the things that I always say is that knowing your ApoE4 is either too much information or not enough information. And the reason I say that, the too much information is because if you know the classic is you give for Christmas or for Hanukkah your relative a kit for a direct to consumer ancestry type, you know, genomics tool. They go online, they find out they’re an ApoE4, that’s all they know. Well, they’re going to get panicked and go, oh my gosh, I’m gonna get Alzheimer’s. So that’s not enough information, because they’re then not knowing, well, what are some of the other things that interact, and there’s a lot of genes that if you don’t have certain genes, your risk as an ApoE4 gets cut in half.  

00:14:37 Julie 

I love that!  

00:14:40 Sharon 

And then there’s other genes that make your risk higher, and so it’s not enough information to know just your ApoE4, because otherwise, what is your choice? Do you want to?  

Do you know 60 different things or 30 different things without knowing if you need to, and if you’re young and you don’t have any cognitive decline, that can be very onerous and kind of really heavy, whereas if you can go oh, I’m a lucky ApoE4, not that I’m going to ignore it and, you know, eat a bunch of sugar and things like that, but if you don’t have some of the other genes that interact with ApoE4 and you know for me, my risks are really mitochondria or my wrists are really choline or my risks are really my detox pathways. Then you can come up with an empowering specific treatment plan to help you stay well, that feels very specific to you.  

00:15:35 Julie 

Oh I love that. I hope you brought some ApoE4 case studies that we can talk about.  

00:15:43 Sharon 

I did and do you want to start with one of somebody who was having cognitive decline and we got better or you want to start with somebody who’s an APOE 4/4 in their 70s and is still doing great? Which do you prefer?  

00:15:55 Julie 

You could go ahead and pick because I think we have almost everyone represented in our community, so any ApoE4 case studies would be great.  

00:16:05 Sharon 

So I’m going to start with a woman who is an engineer, and we’re going to call her Sandy. And for our clinicians, ’cause I know some of the clinicians who watch our party or community may be listening, this is one of the cases we used during the ReCODE Apollo training when we’re teaching on genomics, ’cause it’s such an interesting and, really, a great illustration of why it’s important not to immediately go to somebody who starts having cognitive decline in their 50s, oh my gosh, you might have, you know, APP or Presenilin-1 because a lot of times it’s just a belief or with some other things that kind of happened, and so she came to us because she was 52, an engineer, and was starting to have problems with math. And that is difficult for engineers, and was thinking that she needed to switch careers or retire and was really scared. She is an ApoE4. But again, most people with ApoE4 don’t start having problems until they are in at least their 60s and many times 70s or later. 

So what we did is we did her genomics because that allows us to kind of dig deeper and say well what is going on. And she had some things that we would not have known about. She had a particular mitochondrial pathway. So ApoE4s in general have a lot of mitochondrial issues. It’s a common and one of the reasons is one of the big mitochondrial membrane genes that is important for the health of the mitochondria is right next door to ApoE4, and 75% of the time it’s co-inherited. Meaning, 75% of ApoE4s get this problem with their mitochondria just because of the way the genes are inherited and then ApoE4 can affect mitochondria, but she didn’t have that. 

But instead she had a different mitochondrial problem, and the reason that that’s important is different problems take different solutions, so for people who have mitochondrial membrane issues, things like phosphatidyl choline, phosphatidyl serine, the different membrane lipids like NT lipid factor or ATP fuel can be really helpful as well as giving all the different things mitochondria need, like a K-PAX or a MitoCore or I know that there’s some LifeSeasons products as well that have the acetyl L carnitine and have the alpha lipoic acid and the CoQ10 and all those things. 

But that wasn’t her issue. Her issue was in the ability to make mitochondrial DNA to make the purines. Well if you can’t keep your mitochondrial DNA alive, your mitochondria don’t stay alive and the treatment for that is different because it’s not CoQ10, it’s actually folinic acid and betaine and citicoline that kind of helped push that pathway. So that was we wouldn’t have known that otherwise. 

She also had some pretty significant B12 issues. Being able to carry B12 into your brain is really important. If we measure in the blood B12, you’re going to get different levels, but the carrier for B12 in the blood is different than the carrier in the brain. So 80% of your B12 is this carrier TCN-1, which is in your blood but the brain carrier is TCN-2. So if you have two copies of TCN-2, you need a much higher level of B12 than someone who doesn’t have that because you have to kind of flood the receptors. 

She also had problems with vitamin D, which is relatively common, and then had some different problems with detox pathways. And again, depending on what detox pathways are affected, we have different ways of modulating them with glutathione, with N-acetyl cysteine, with even rosemary up regulates certain of the detox pathways. 

And so we kind of just went through all of her DNA. We did also – she was new. She was not a member of your community. She didn’t understand that diet has a huge effect on ApoE4, so we helped her change her diet to a mild ketotic diet, and she responded great. Literally, within three months she was feeling so much better and able to feel comfortable that she’d be able to stay at work. 

And so, but really some of those key pieces were ones we wouldn’t have been able to measure in the blood. Oh, the other one that she had that we wouldn’t have been able to measure in the blood is the ability for the brain to convert thyroid hormone to its active form. Thyroid T3 in the blood does not relate to T3 in the brain, and I think that’s a really important fact here is that you can measure something in the blood, but because of the blood brain barrier, it’s not the same. And every tissue – your bones, your heart, your kidneys, your brain – they all have different expression of DNA. 

And then the last one she had, which was I would say that the mitochondrial thing and then this are probably the most important was she had something called a TNF alpha promoter SNP, and, have you heard of a promoter, Julie?  

00:21:17 Julie 

Yeah, but explain what that is for our listeners.  

00:21:22 Sharon 

Yeah, so genes, we don’t want our genes on all the time. It’s kind of like you wouldn’t want everything electric in your house on at once. It would create chaos or in the world, so we have these things called promoters which are basically on off switches in front of our genes and her TNF alpha promoter was way too active. So it’s kind of like always having the light switch on. Well high TNF alpha will cause not only inflammation in the brain, but it leads to almost destruction of tissue if you get too much inflammation.  

And lion’s mane, for example, is really good at turning off TNF alpha expression, lowering it. And there was a study done in Japan using lion’s mane in people who had mild cognitive impairment and at the end of this study, just giving lion’s mane, and they didn’t have the genomics, but in this study they showed that 72% of the people who got two grams of lion’s mane a day had an increase in their score – it was kind of like a MOCA but a Japanese equivalent, so, memory test – of three points or more and 27% had an increase of two points or more and in the placebo group it was the opposite. 70% of the people in the placebo group had no improvement or zero to one, and only 7% had an increase of three points or more during the course of the study. 

So you know, we think about the drugs that were recently approved for Alzheimer’s that showed 20% less worsening of cognition. Can you imagine if a drug showed that 70% of the people got three points improvement on a 30 point test?  

They went from an average of 23 to an average of 26, which is a huge difference, and so for her, that was another really important one, adding the lion’s mane. And so again, we were able to get her feeling comfortable. She was one of our first patients, so that was three or four years ago, and she’s still doing great. She barely needs us anymore because she now knows what to do for her body.  

00:23:29 Julie 

I love that! That is such a hopeful example. You mentioned you have another example of somebody who’s using this for prevention.  

00:23:39 Sharon 

Well, I have a woman who came to me – and I have quite a few APOE 4/4s all doing great. So first of all, that’s really helpful. And one of them is about 67. The other woman is 79 and she’s still doing perfect. I mean, her cognition is probably as good as mine. I mean, she is amazing and very, very with it. And so when you get these people and you go, well, she’s APOE 4/4 and she didn’t even know she was an ApoE4. 

So this woman came to us, and her main complaint was fatigue. She’s 77 years old when she came to us and now I think she’s 79. And she came because she wanted to optimize her health. She mostly was feeling tired and she was having trouble losing weight, had a little bit high blood sugar, had high blood pressure that was hard to control, so some just kind of normal things that people worry about in their 70s as they get older and we did her genomics because it can help also with optimizing blood sugar, understanding why your blood sugar goes high, understanding your cardiac risk, and so we were really surprised when it came back, and it showed that she was an APOE 4/4 because she wasn’t complaining about cognition. And so I asked her, are you having any cognitive impairment? She said, well, you know, I mostly just feel tired, I wouldn’t really describe it as brain fog. And at that point we’d already given her vitamin D because I had some blood work back and I had given her mitochondrial supplements because what she was describing with that kind of fatigue and she also had a little bit of just sensations in her legs, which is common in people who have mitochondrial things. Their nerves just don’t feel right.  

But her MOCA was perfect and, well, I think she had a 29, but that’s still very good, obviously. And so then I dug into her DNA to go, this is really interesting – let’s look at why you’re doing so well, and there’s quite a few genes that work in combination, so MTHFR works in combination with certain inflammatory genes and that TNF alpha works in combination so TNF alpha and ApoE4 can have a huge additive effect in some people, dramatically increasing the risk. Again, there’s a gene in a cholinesterase pathway, so – you guys heard of acetylcholinesterase – well, there’s other cholinesterases that relate to how these brain chemicals are treated, and she had really none of the ones other than one copy of 1 mitochondrial one that interact with the ApoE4 to cause additive risk, so that made her actual risk much lower than a typical APOE 4/4.  

So I have patients who came to me really terrified in their 50s, or whenever, because their cardiologists or their regular doctor did a Boston Heart or a Cleveland Clinic, and they go oh, and by the way, you’re in APOE 4/4 without giving him more information. And they look it up and they go. oh my gosh, I’m gonna, you know, get Alzheimer’s.  

But we were able to kind of say hey look, let’s make sure we do things to protect your brain, but you’re doing really well. Let’s understand why you’re doing well, and then let’s say, what do we need to do to ensure that that’s going to continue? And it’s not that taking 20 or 30 or 40 supplements is necessarily bad for you, but number one, it’s expensive. And if you don’t need to, if some of those aren’t necessary for you, because you’re really good at making choline or because you are great at transporting B12, or you don’t have the mitochondrial issues as much as someone else, you might not need as much mitochondrial support. It’s just nice to be able to kind of be more selective and there’s a lot of other pathways that contribute as well that we haven’t even talked about like hormone pathways. And you know, different inflammatory ones.  

00:27:49 Julie 

Absolutely. I mean, you’re taking precision medicine to a whole new level. 

There’s a case that I’m following where they just ordered an IntellxxDNA report. It’s a woman with mild cognitive impairment who’s several decades post menopause, and her practitioner put her on estradiol. And she’s having hot flashes in response, and they can’t quite figure it out. So somebody thought, let’s order IntellxxDNA, so I’ll be very curious to see how that plays out.  

You, you’ve totally convinced me and I’m going to go ahead and run my own genomics. And if you’re willing, let’s go ahead and make a Part 2 of this discussion, and maybe you can share some highlights from my report so that our listeners can see in real time how my protocol might change or how I might be able to fine tune it based upon my results.  

00:28:47 Sharon 

Absolutely, and one of the things Julie that you and I had talked about that I think we do want the audience and your listeners to understand is IntellxxDNA has so much information in it. It has things not only about supplements, but things about medications. It gives dosing of supplements. It links to thousands of studies. It talks about things like brain ischemia, which is kind of like the stroke risk with different coagulation factors of blood clotting risks.  

So it falls under a little bit different FDA category than any of the direct to consumer genomic tools.  

It’s what’s called a clinical decision support tool, which means IntellxxDNA can only be sold to a licensed healthcare professional – an MD a DO, a naturopath, a nurse practitioner, a PA. So we understand that there are lots of people who want this information, but know that what your listeners will have to do is either reach out to IntellxxDNA and we can let them know people trained already in their state or we are happy as kind of a special for your listeners if they have a doctor that’s been working with them on their brain protocol or a naturopath or a licensed healthcare professional … if they let us know that they’re part of your ApoE4 community and that they refer their doctor, we will give their doctor online access to training. We will waive the training fees. We don’t want people to have to switch their doctors or switch their healthcare provider. So we will give them free access to our online training and we also help train our clinicians. We actually walk them through their first three reports so that they can feel 100% comfortable that they’re giving as good of a consult with the first report as they are with their 100th report. 

So don’t be afraid to reach out to your clinician. Most of them will have heard of it, and maybe be kind of waiting and going, I don’t know, do I want to do this? Do I not? ‘Cause it does take a little bit of time on the clinician’s part to learn. I can pretty much guarantee that once they start using it, they’ll be like, oh my gosh, this is getting outcomes is so much easier and that they will love it, but know that they’ll get a chance to work directly with me and with our research team so that we will help make sure that your community patients all get great responses and understanding.  

00:31:17 Julie 

Thank you so much. That is very generous. 

So you’ve covered some really important stuff – we can’t order a report ourselves. We have to go through our practitioners or identify one of your providers and many of them do telemedicine, so geography shouldn’t be a limiting factor.  

00:31:40 Sharon 

We do on our website have a little sheet you can download and take to your doctors. Saying, here’s some information about it, because sometimes if they haven’t heard about it, they’re like, oh, you know, I tried some of those genomic tools. It didn’t really give me any information. 

Well, they weren’t legally even allowed to give information because if you sell to the consumer, but also we took many years and many millions of dollars to build a tool useful for functional and integrative trained providers and particularly ReCODE providers because I was in the middle of building it, I’d just built heart disease and macular degeneration, when I was presenting about the CIRS as it was called at that time, the mold issues, at the conference at the Buck Institute where you and I met, and I went up to Dale and I said, hey, I’m thinking of adding all the cognition into our genomics. Can I make it kind of match to be supportive of the ReCODE providers because I can include the BDNF and the choline and the hormones and the mitochondria and the CoQ10 and all those things. And he was like, of course! 

You know, he always says if somebody is going to do something that’s gonna help, I’m agnostic. We’re all here to try to help people, and so this was built to help clinicians. And of course it helps patients. But we want to work as a team, but there is a sheet you can take to your clinicians.  

On our website there’s some podcasts and webinars if you want to listen, like Dr. Crag Tanio who is one of the ReCODE providers. He did an interview specifically about how he’s using it. We have ones that you can watch that are video, so please feel free to to link. 

00:33:33 Julie 

Definitely, yeah, we’re going to go ahead and link to your website so people can go ahead and look through all of your information. And you are so right that the practitioners who do become trained with IntellxxDNA are hooked. I’ve heard very very positive things. And Dr. Bredesen is more than agnostic. He’s actually used your tool in his most recent clinical trial, which he’s still writing up, so that’s very exciting.  

00:34:03 Sharon 

And we have we have a link to that preprint on our website as well, because that preprint is available. And yes, we were of course honored to be the genomics tool that he chose to use as part of the study. 

And one of the things that Dr. Bredesen will tell you is, in the study, there were just some really interesting cases where, like a gentleman who was flying from California to Asia – this was before COVID – on a regular basis and he would get worse cognition every time he would fly. Well, we were able to identify what was going on with him that was causing that, and again, it was something that was more related to brain ischemia, and then we were able to reverse it. 

So we’re not at the end of genomics by any means. We’re still the beginning of our understanding of how we can use personalized medicine, but we do address many, many hundreds of SNPs that allow you still to have a much more personalized plan of understanding.  

Are you someone that has horrible detox pathways, but it’s not just one detox pathway? There’s some that are modulated by vitamin C, some that are modulated by glutathione, some that are modulated by NAD, and NAC, and sulphurophane. So it really helps personalize even within a subset of being a Type 3, well. which kind of toxins do I build up and why?  

00:35:34 Julie 

Right, I’m very excited to have my own genomics done, and I love that you mentioned we’re really at the infancy of understanding how this affects health, so I assume that your research team is always reading new papers and updating your reports.  

00:35:51 Sharon 

We are, so there’s two different ways our reports get updated. So for example, I was working reading and there is a transporter of amyloid that we didn’t have in our report, but we have it on our array. We have it on our backbone. We have a few hundred thousand things we could talk about. Can you imagine if we gave a report that had 200,000 pieces of data? No one would want it, but this one was important because it turns out that it’s involved in removal of amyloid from the brain, and it’s associated with increased cognitive impairment in Alzheimer’s, but also persistent Lyme. Well, that’s like a really important SNP and it gives you three times the chances of having ongoing symptoms after having had Lyme disease, because it kind of traps stuff in the amyloid biofilm. Amyloid can be part of a biofilm itself, and so we just added that this week, and so we’re constantly adding new things. 

And then we also for people who have different things going on will have additional kind of add-on reports, so not so much in the ApoE4 world but for example we have a mental wellness report that is more geared at psychiatric things like OCD and anxiety and depression and stress and ADHD, which of course we all have those as well and then we have an add-on report for children with neurodevelopmental disorders like autism.  

And so we’re in a lot of different topics and constantly ongoing research right now further into Lyme and mold and chemical sensitivity. And there’s so much that we can study. We’ve got hundreds of things to study. It’s all a matter of time and energy and funding and all that.  

00:37:40 Julie 

All of the things you mentioned, the Lyme, the Lyme coinfections, the mold, affects so many members of our community, so I can’t thank you enough.  

I encourage everyone to check out our show notes. We’re going to have a transcript. We’ll have more information. And we will have a link to Dr. Sharon’s site. 

So thank you and goodbye until our next podcast.  

00:38:04 Sharon 

Thanks, Julie. Thank you so much for having me.  

00:38:07 Julie

Yeah bye bye. 

Subscriptions are available on many platforms including

Dr. Dayan Goodenowe joins Julie Gregory to discuss his new book, Breaking Alzheimer’s: A 15 Year Crusade to Expose the Cause and Deliver the Cure. He talks about how his research lead him to plasmalogens and how they relate to neurological health. He explains what goes wrong biochemically as dementia develops and highlights age-related diminishing plasmalogen levels as a major driver of disease. He outlines his research showing that ApoE4 carriers may require more plasmalogens to maintain cognition, and he identifies tests and supplements to support plasmalogen levels. Finally, they discuss the unprecedented results of Dr. Goodenowe’s newly completed clinical trial that he just reported on at the Alzheimer’s Association International Conference.

Podcast Part 1: Plasmalogens & Neurological Health

Educational Seminars: free registration

Prodrome Sciences: supplements and tests

Breaking Alzheimer’s book: direct / Amazon

More info: DrGoodenowe.com

For pre-publication discussions of clinical trial results sponsored by the Alzheimer’s Association and presented at the Alzheimer’s Association International Conference (AAIC) in July 2021, watch episodes C105 and C106 at Dr. Goodenowe’s Educational Seminars site after free registration.

0:22  Julie’s introduction of Dr Goodenowe :  This is a longer podcast, almost 1.5 hours, but full of information, including results of his recent clinical trial.

Dr. Goodenowes’ research into biochemical mechanisms of disease started in 1990.  His curiosity on the biochemistry of life remains insatiable.  In the last 30 years he invented and developed advanced diagnostic in bioinformatic technologies, designed and manufactured novel and natural biochemical precursors, and identified biochemical prodromes of numerous diseases including Alzheimer’s Disease,   other dementia’s, Parkinson’s Disease,  multiple sclerosis, ALS, and many more.

Dr Goodenowe is now going beyond disease and the detection of biochemical dysfunctions to diagnose and move toward correction of biochemical dysfunctions to treat disease.  His new focus is to defeat the entropy of aging by creating strategic biochemical and biofunctional reserve capacity in advance of known disease risk so the body can maintain the physical and biological functions of life indefinitely and without disease.

2:06 Julie:  Welcome Dr Goodenowe.  So much has happened since last podcast, a recent achievement includes the publication of a new book, Breaking Alzheimer’s.   It was an excellent read and as a layperson you made it very accessible.

3:04 Dr G:  I’m a generalist in many areas.  My value is to consolidate research from multiple avenues, even though I’m an expert in specific fields, particularly biochemistry.

It’s easy for scientist to get enamored with the complexity of science.  There are basic organizing principles that are common in everyday life.  People get intimidated by science, that it’s complicated. But most of the things in science follows general logic that we see in everyday situation.  The words change, get more complicated, but the basic underlying principles are the same.  I really wanted to break down this fear of science.  I try to teach people how to learn these principles.

The last chapter goes into why we don’t have cures for these diseases, the structural reasons. Not to blame anybody, but to understand the organizational infrastructure of medicine and how private industry works vs public industry, and why universities aren’t doing public work anymore.  Many supplements have been clinically validated over the years yet they’re not implemented into routine care.  Why?  I explain that and if you want to change this reality, you have to understand what it takes to implement change.

I come from large clinical trial work, I also come from the pharmaceutical industry.  There are certain rules of the pharmaceutical industry and certain aspects of clinical trial work that have real validity, we can’t throw that out when we get into nutritional based medicine.

My interest is population medicine.  Medicine that can be applied to entire populations to change the percent of people who get dementia, or cancers, or autism.  That’s my passion.

I’m like a farmer of humans and giving them the appropriate fertilizer.

7:31  Julie:  You’re doing an amazing job of bridging several camps, we need more like you.

In your book you describe yourself as a biochemical detective.  You discuss the mass spectrometry technology platform that you invented that ultimately led you to identify plasmalogens as a major player.  Tell us how plasmalogens emerged from among the thousands of other biochemicals that you were studying.

8:04 Dr G:  I fundamentally view our living world through the lens of chemistry.  There are three large organization principles:  biology, chemistry, and physics.

We live in a world of chemistry.  We’re controlled by very simple laws.  The first law of thermodynamics is that energy or matter can neither be created or destroyed.  We just move things around.  Sunlight comes in, it converts carbon dioxide and water into glucose in plants. Then we take that and we burn it up with carbon dioxide and water.  We’re just moving electrons around, we’re moving atoms around.   That’s chemistry.

When the genetics revolution occurred in the 90s people sequenced entire genomes of plants and animals, thus understanding how these systems work.  Chemistry is really that core.  We needed a technology that could measure comprehensively all these small molecules so that we could see these transformations, so we could see this first law of thermodynamics in action.

Disease simplified is that something changes, there’s a cause and effect.   The technology that I invented was called nontargeted metabolomics, using high field mass spectrometry.  This allowed us to measure thousands and thousands of molecules simultaneously.   The original concept was to study biology, chemistry, and the effects of genetic modification of plants and animals, then apply it to human biology in human diseases.  When we started to apply it in the clinical trial world we looked at different disease states, what’s different.  Because if I can physically see a phenotypic difference, for example, you’re healthy but your sister has ovarian cancer I can ask what is different?  If I can physically see something different there has to be a chemical signature that matches that difference.

11:30

Over many, many diseases we started to see very powerful diagnostic capabilities.  Virtually every single human disease is diagnosable with this type of technology, the prodrome scan technology.

When it was applied to Alzheimer’s Disease, we saw these molecules called plasmalogens decrease.  Not just plasmalogens, many others too.  That’s the challenge of science, the cause and effect relationship can be quite diverse.  The farther you get away from an event, the harder it is to identify the actual cause.  For example, radiation disease in people from Nagasaki or Hiroshima 20 years after the nuclear bomb.  If you didn’t know about the nuclear bomb you’d have a very difficult time figuring out why the damage occurred.  The farther you get away a causation event the more complicated the situation gets.  With one insult in the human body, you get primary effects and secondary effects and over time you have thousands and thousands of changes.  The challenge is to work your way back up to that simple event.

It became reproducibly observable that plasmalogens were deficient in Alzheimer’s disease and cognitive impairment.  The low levels of plasmalogens correlated with the severity of the cognitive impairment.  It correlated with the rate at which it declined.  It also correlated with who got dementia in the future versus those who did not get dementia in the future.

From that clear observation the question is why?  What is it about plasmalogen deficiency?  Also is it linked or is it just a symptom?  With more and more research it became obvious it was core.  Even post-mortem analysis of brains the plasmalogen association with cognition is the most strongly associated.  It is the closest to the event we’re measuring, which reduced cognition of anything else in the human body.  That’s how it came to be.

14:12

This revealed that biochemical deficiencies precede our diseases.  They are prodromes, they are predictive of future events. The body can tolerate dysfunction for a certain period of time but eventually it turns into disease.

14:56 Julie:  You describe Alzheimer’s as a plasmalogen deficiency.  Is it really that simple?  Can we just replenish our plasmalogen levels and be protected?

15:10  Dr G:  To a certain degree, yes.  Obviously, there are other aspects that contribute.  When we get older, we’re talking 50s and 60s, our brain starts shrinking.  We get focused on Alzheimer’s as being the main event, but it isn’t the main event, it’s brain shrinkage, neuropathologies, reduced brain health.   Alzheimer’s is just a symptom.  Alzheimer’s is not a disease at all.

Your body is designed to work in a certain balance.  Your body must make your own plasmalogens and you make a lot of them.  Probably 20% of all lipids in the body are plasmalogens.  When you lose plasmalogens you don’t just lose plasmalogens.

For example, you want to bake your favorite cake.  Your recipe calls for 2 cups of milk, 4 eggs, and a pound of flour.  But you don’t have enough milk, only 1 cup.  So instead of a whole cake you make half a cake with the 1 cup of milk, 2 eggs, and a half pound of flour.   You adjust because of the situation.  That’s what your body is doing every night when you sleep.  It’s making “cakes”.  When you’re baking something, that’s chemistry.  You’re chemically transforming something from one form to another.  The egg that’s in the shell is very different chemically than the egg that’s been baked in the cake.  That’s what your body does.  We have trillions of cells in the body and every single cell has “bakers” in them.  These “bakers” are making membranes, proteins, etc.  They can only make what they need to make from what’s in their pantry.   When you lose plasmalogens in the human brain, you don’t just lose plasmalogens. Those “bakers” can’t make things appropriately.  You lose other things:   phosphocholines, ethanolamines, cholesterol, and hormones.  Those all come down because your body will adjust to the materials available to it.  That’s why brain shrinkage occurs.  There’s obviously other aspects, but plasmalogens are a critical component of brain health in terms of synaptic function, membrane modulation, etc.

19:12

The human body is really a very simple design biologically, two core things that must work to live.

This first core aspect is energy generation.  We breathe in molecular oxygen to burn hydrocarbons, much like the car uses oxygen to burn hydrocarbons. We eat fuel: carbohydrates, fats, proteins we burn those into carbon dioxide.  Our lungs are gas exchangers, we breathe in oxygen, we breathe out carbon dioxide.  That oxygen gets neutralized to water in the energy process and is peed out.  That process generates high energy electrons.  We’re basically returning the electromagnetic energy from the sun back.  Plants absorb electromagnetic energy and we release it back.  When the mitochondria of our cells don’t do that properly, we get oxidative stress and these electrons leak out.  One of the consequences of this oxidative stress is inflammation.  Inflammation comes from oxidative stress not the other way around.

The second thing is your lipid membranes.  The human body is made of lipid membranes, that’s why we’re not soup, it’s what gives us physical structure.  We have trillions of cells and each of these cells are defined by their three-dimensional structure and what puts the walls together are these lipid membranes.  The proteins in your body are embedded in these membranes.  Virtually everything lives in lipids in the human body.

Imagine walking on solid ground versus walking in mud.  In mud you can’t move properly.  Walking in mud changes how we walk, how fast, and such.  When we lose plasmalogens your membranes become like walking in mud, nothing works properly.  It’s more than just plasmalogens, there can be other deficiencies, but plasmalogens are critical.

It takes a triage perspective.  You want to first identify the most critical component first, then move on to the next one, and on. So if you’re a gardener, the first thing when you need with a plant is nitrogen and water, not fungicide or sulfur.  After the most important components are taken care of, then you can move on to other things for optimization.  It makes no sense to focus on the minor esoteric issues until you deal with the core issues first.

23:28 Julie:  And that’s plasmalogen levels.

23:31  Dr G:  Plasmalogens are core.  If you don’t have sufficient plasmalogen levels, you’re really wasting your time on a whole bunch of other things.  If you don’t have proper mitochondrial utilization, you’re wasting your time.  You’re fixing windshield wipers on a car that has no oil, it won’t help you drive any farther.

23:53  Julie:  I love your analogies. That’s a very hopeful answer, so yes it really is that simple.  We can replenish our plasmalogen levels, we’ll talk about that later.

In your book, you emphasize the importance of identifying and addressing the APOEε4 mechanism that increases our risk.  You say that’s an impaired cholesterol transport system.  The antidote you suggest is to rebalance the cholesterol transport weakness through high levels of plasmalogens.  Can you explain how that works.

24:38 Dr G:  I really put time toward the ε4 community because it is such a confusing world out there.  This definitive lecture series that I’m launching, the first lecture is on APOEε4.  In the book there three chapters dedicated to the ε4 scenario.  It’s easy to get caught up in the noise.  Just like plasmalogens, you have to identify what is it about ε4, ε3 and ε2 that changes the risk profile.  Everyone with the APOEε4 genotype should understand is that the ε4 genotype itself has no increased risk of mortality in the nature of the genotype difference.  There’s no reason for an ε4 carrier to live less than an ε2 or ε3.  Similarly, people with the BRCA gene with regard to breast cancer, BRCA does not change your mortality risk, it just changes your disease risk.  It’s the disease that provides the mortality.  I go through that in the book.

The most proximate issue as a consequence of the ε4 genotype is accumulation of amyloid.  So ε4 carriers accumulate more amyloid than non-ε4 carriers.   ε2 carriers will accumulate less amyloid than ε3 carriers.  If you know the amyloid level of an individual, their genotype is irrelevant.  It’s the risk of accumulating amyloid.

Why do we have amyloid?  It’s a marker of brain health.  It’s all related to cholesterol transport.  Your body transports cholesterol on lipoproteins.  Cholesterol is a big piece of fat that isn’t soluble in water.  So how do you transport it because the body, blood, intracellular space are all made of water.  The body sticks it to highly water-soluble proteins called lipoproteins.  These lipoproteins are fat transporters.  The APOE gene codes for one of those proteins, the Apolipoprotein type E (ApoE).  It’s a very minor protein, we’ve known about it since the 70s.  The genotype has been known for many years but it wasn’t until 1993 that it was published that 50% of the people who had Alzheimer’s in their family history had the APOEε4 genotype.

In the United States about 25% of the population has one or two ε4 alleles.  Around 60% to 65% have two ε3s, and 10% to 15% have an ε2 allele.  These are the three main groups (ε4, ε3 and ε2) and there’s a high prevalence of Alzheimer’s in those with the ε4 genotype.  Why is that?

The ε4 lecture goes into this in greater detail with literature references.  But if you’re an ε4 carrier and you get a blood test, you’ll notice you typically have higher levels of LDL versus others.  If you’re an ε2 genotype you’ll typically have lower levels.  That is not bad, that is completely irrelevant to your health.

29:32

The reason isn’t the circulating ApoE4 levels, less than 5% of the lipoproteins in the periphery of the body is ApoE, virtually none of it is in LDL particles, but in Apolipoprotein B (ApoB), which is LDL.  Apolipoprotein A (ApoA) is HDL.  A little bit of ApoE is found in HDL particles, a little bit in very low density LDL, and a little bit in chylomicrons.  What makes ApoE unique is because whereas it makes up only 5% of the lipoproteins in periphery: lungs, liver, blood supply, etc., most is in the brain, it’s the only lipoprotein that the brain makes.  The brain has a totally separate cholesterol regulation system.  None of the cholesterol from your liver and blood supply gets to the brain.  Your brain makes all its own cholesterol and all its own transportation of cholesterol.  In the periphery we have an interstate system called the circulatory system: blood, veins, and arteries, that distributes material all around the body.  The liver makes most of the cholesterol and distributes it on LDL particles.  The cells will absorb the cholesterol that they need from the blood supply.  When you get a blood test it’s measuring total cholesterol, HDL, LDL.  Every single cell in the body can make its own cholesterol and the body will balance it, redistribute it.  If it’s making a lot, it won’t pull much from the blood supply, if it’s hungry, it will pull from the blood supply.

The reason why APOEε4 carriers have higher levels of LDL cholesterol is that they’re cholesterol conservers, which means your cholesterol efflux is lower.  Imagine your house has solar panels on an electrical grid.  The electrical grid from the power company is the circulating LDL.  The electrical grid in your house powered by the solar panels, that’s your individual cell.  If you’re a APOEε4 carrier, you’re very energy efficient, you don’t require much energy from the power company, so you absorb less, you conserve cholesterol.  Since you conserve cholesterol, you don’t require as much from the blood supply, so LDL levels will elevate because the cellular demand of cholesterol is less in an ε4 carrier than in an ε3 carrier.  ε2 carriers are the opposite, they efflux cholesterol, they can’t hold their cholesterol, they’re always absorbing cholesterol from the blood supply which makes their LDL levels low.  ε4 carriers have low cholesterol efflux, they hold their cholesterol better.

33:34 Julie:  They hold cholesterol better in the periphery, what about the brain?

33:38 Dr G:  That’s where it gets interesting.  They do the same thing in the brain, but the brain is very different.  In the periphery you have the interstate system of large arteries.  The brain is like Chinatown, it’s a whole lot of little streets, there’s no real circulatory system.  There’s a bit of a tidal system with the cerebral spinal fluid.  Everything in the brain is local.  What makes ApoE such a unique molecule, it has equal LDL and HDL qualities.  It can act as an LDL so it can deliver cholesterol and it can act as HDL for exporting cholesterol.  Your brain uses ApoE for both functions.  Instead of the liver making cholesterol, in the brain your astrocytes make cholesterol and your neurons and everything else absorb cholesterol.  It’s all about cholesterol efflux.  How the brain uses one single protein (ApoE) to do all of this is with different transporters.  You have LDL transporters which are generic, but how cholesterol gets out of the cell requires three main transporters called ATP binding cassettes (ABC): ABCA1 (A1), ABCG1 (G1) and a ABCG4 (G4).  Three separate transport proteins the control the efflux, some are on neurons, some are on astrocytes, and they work in conjunction with each other.  The APOEε4 genotype is involved in the efflux from A1.

The APOE genotyping is called Single Nucleotide Polymorphisms (SNPs – pronounced snips).  There are two amino acids that are changed.  They change from either a cysteine, which is a sulfur containing amino acid, to arginine, which is a very polar amino acid.  What’s important about cysteine, as a sulfur amino acid, is it creates disulfide bridges, dimers, which are like two magnets that stick together.  APOEε4 carriers cannot do that, they can’t create dimers.  The ε2 carrier will have two cysteines, two free sulfurs.   ε3 carriers will have one sulfur cysteine and one arginine.  ε4 carriers will have two arginines, which means they have no cysteines at all, they cannot create dimers.  It’s the dimerization of the ApoE4 protein that modulates its cholesterol efflux capacity through A1, and it’s a dose dependent effect.

The difference between the genotypes is the ability for cholesterol to leave the cell through the ABCA1 transporter.  That A1 transporter is in a certain part of the membrane, in the phospholipid rich region.  The other system that modulates this A1 transporter is an enzyme called ACAT (Acetyl-CoA acetyltransferase), it’s what esterifies cholesterol for export.  That’s used in the periphery as well.  What happens is that protein is controlled by plasmalogen levels, so if you increase cholesterol esterification it increases transport.  You have a three-legged race with ApoE on one side, plasmalogens on the other side, and the A1 transporter in the middle.  If one is weak, the other can compensate.  So when we’re young with lots of plasmalogens, APOEε4s are protected, it only becomes a risk factor later in life when plasmalogen levels become depleted, then the counterbalance of the ε4 on the ABCA1 transporter is missing.  When that happens, the levels of cholesterol in your membranes increase and with that amyloid, the Amyloid Precursor Protein (APP) is shifted from its normal process which is the formation of soluble APP to Amyloid Beta 42 (Aβ42), a major component of amyloid plaque.

That’s why ε4 carriers have an association with amyloid.  ε2s will have less amyloid than ε3s, ε4s will have more amyloid than ε3s (ε2 < ε3 < ε4). It’s 100% related to cholesterol efflux.

If an ε4 carrier does not accumulate amyloid, that person is just like anyone else.  An ε3 carrier can have other cholesterol problems, have more amyloid, and be worse than an ε4 carrier.  Even an ε2 carrier can have amyloid issues.  It’s just that odds are, all things being equal, and the individual is ignorant of what controls their genotype, then ε4s will have cholesterol membrane problem.

So ε4 carriers that have high plasmalogens in the brain have normal amyloid levels. If the blood plasmalogen levels are high, the ε4 genotype is silenced, no increased risk.  That was published a year and a half ago.  It all comes down to that one protein the ABCA1 protein, it’s related to the dimerization, specifically the SNP mutation in ε4.   ε4 carriers don’t need to know anything more than that.

The LDL in your blood makes no difference, there’s nothing wrong with that, in fact it’s a measure of health.  The worse thing is to have low cholesterol because it shows your cells are unhealthy.  If your cells are unhealthy, they need cholesterol and they suck cholesterol from the blood supply, or your liver is not making enough cholesterol.

When the A1 protein doesn’t work properly the problem is distribution.  Everything in the brain is localized.  The neurons share with each other.  If one neuron has a little extra cholesterol, a little extra phosphorylcholine, it will export it.  It’s like a solar panel network.  The power is redistributed as needed, but if you can’t redistribute, you can’t optimize.  That’s what happens with APOEε4 carriers, the reserve, or buffer, of redistribution is not as good.  We’re very dependent on having adequate plasmalogen levels whereas the ε2 carrier can be sloppier.  It’s like how one person can eat and remain skinny whereas another person can look at food and gain weight.

42:16 Julie:   It’s actually very hopeful.  So as an APOEε4 homozygote (ε4/4) as long as my plasmalogen levels are high, my cholesterol efflux in my brain will be optimized, and I will not collect amyloid beta.

42:25 Dr G:  You’ve made it this long; your body has the right compensation mechanisms.  That’s the other problem with have with medicine and diseases, they get focused on excesses.  But that’s not how health works, 100% of human disease is caused by a deficiency.  Excesses come from deficiencies.  If you have a deficient transport of the A1, that creates the excess of cholesterol.

43:34 Julie:  That’s what I don’t understand.  I’m thinking of a Type 2 diabetic taking in an excess of glucose, isn’t that what’s causing disease?

43:45 Dr G:  No actually, it’s because they have an impaired ability, it’s insulin insensitivity.  The reason why they have elevated blood glucose is because they have a deficiency in glucose regulation, that deficiency causes the excess.

The world is very stingy.  Biochemistry doesn’t waste anything.  Excess isn’t created freely, if there’s excess, it’s because there’s nowhere else for it to go.  The root cause of all toxic excesses comes from a deficiency of some system.

45:02 Julie:  I’m going to go back to cholesterol because I think a lot of people in our community are uber focused on their cholesterol.  There’s something you say in the book that’s every encouraging.  In terms of all-cause mortality, you say total cholesterol in the 220 to 240 range as being the healthiest.

45:30 Dr G:  240-250 is where you want to be.  That’s not me saying that, that’s 164 country epidemiology data, 12 million people in Korea, these are huge studies.  The optimal blood cholesterol level for longevity, lowest rates of all-cause mortality occur in individuals with cholesterol levels in the 240 range, 220 to 260.  As soon as your cholesterol levels get below 200 all-cause mortality starts going up quite dramatically, it’s an indicator of reduced health.

46:12 Julie:  It fits with your stingy analogy.

46:16 Dr G:  Cholesterol is critically important to the human body.  We want to regulate it, too much in the wrong place is not good. For instance, what we talked about with too much in the membrane of the brain.  Typically, if people have low levels of cholesterol in their blood it indicates something is not right. Either they have a liver problem in that they can’t make enough cholesterol, often it’s a phosphatidylcholine deficiency that’s causing it, or they have cellular issues.  If they’re taking a statin, basically a statin is a mitochondrial toxin, it turns off your solar panel, it forces the cells in your body to get their cholesterol from the blood supply.  Since the cells can’t make their own cholesterol, they’re forced to get it from the blood supply, which lowers blood cholesterol levels.  Where statins got their main purpose is in cardiovascular disease.  Oxidized LDL is associated with atherosclerosis and heart disease.  The theory with statins is if you lower LDL, you lower the pool of peptide of proteins that can be oxidized.  That’s logical and it’s true.  The clinical data on statins is if you have underlying oxidative stress, if you have high C-reactive protein levels and high LDL, then you’re at increased risk.  But if your oxidative stress markers are low, you can have cholesterol of 300 and it’s not going to hurt you.

48:07  Julie:  Wow, that’s very encouraging.

48:11 Dr G:  Cholesterol is not a toxic molecule, it’s benign, your cells need it, by itself it has no toxicity.  If it gets oxidized then it becomes an inflammatory mediator, it creates foamy macrophages, atherosclerotic plaque, etc.  The issue is really oxidative stress, it’s keeping C-reactive protein levels down.  That was another outcome of the clinical trial is that people who take plasmalogen have low levels of oxidative stress.

48:42 Julie:  That’s so exciting.  Before we get to the clinical trial results you recently presented, I want to tie this in a neat bow so our listeners know.  We’ve talked about plasmalogen levels and that we can increase levels, I want to tell them how to do it.  You’ve created a Prodrome Scan that can be very helpful in learning plasmalogen levels and other things as well.

49:12  Dr G:  The Prodrome Scan is the beginner’s kit of your own personal biochemistry.  It identifies the key issues of biochemical health that you want done first.  It’s really basic stuff.  Looks complicated the first time you see it, but it’s really basic. It’s organized into two pages, 14 sections.  One section deals with the phospholipids of the body, part of that is the plasmalogens.  The other is phosphocholines, people talk about lecithin, it’s another major issue in society that people, especially vegetarians don’t get enough good fat.  Choline deficiencies are really bad, that’s one of the reasons you have low cholesterol, it causes liver disease, pancreatic cancer and so on.   You don’t want to become choline deficient. It’s also linked to your homocysteine system.  We look at phosphocholines and ethanolamines the stuff that makes up all the membranes of the body.

Then we look at fatty acid ratios in the lipids.  We know about omega-3s and omega-6s and omega-9s and saturated fats.  The same part of the call that makes plasmalogens makes your own DHA, which is your long chain omega-3.  You want to make sure your cells have sufficient DHA or actually high levels of DHA in relation to arachidonic acid (AA) which is your omega-6 version.  We measure those levels in the membrane lipids, so that your cells are pre-loaded for low inflammation.  You’re going to get inflammation, that’s natural, you want that inflammation to stay localized and then disappear after it does its job.  The problem with the inflammation that people are experiencing with autoimmune diseases is that inflammation doesn’t stay localized to that site of inflammation, it grows.  Part of that is making sure your DHA to arachidonic acid ratio profiles are right.  It’s also very important for cancers, especially for reducing breast cancer risk.  Also cardiovascular risk.

51:47

Then we check iron levels.  If you’re iron deficient, then you become deficient in other key metals.  We need iron for oxygen transport.  All the cells, the mitochondria, need iron.  Most of the mortality from COVID in hospitals are from people who have a pre-existing iron deficiency.  When you get inflammation, your body is making a whole bunch of new cells, in the brain it’s called microglia, and in the blood it’s your macrophages and T-cells.  Those are brand new cells.  For every cell that your body makes there has to be materials to make them, you need “bakers” all those cells need mitochondria, peroxisomes, etc.  Those cells need iron. Mitochondria need iron.  When you get inflammation, it starts sucking iron out of your reserves. If your inflammatory cells need iron they take it out of the other cells. You don’t want to become iron deficient or deficient in the other metals that follow such as like selenium and copper that I don’t measure, but there are other tests can measure for that.

53:14

I check gastrointestinal (GI) health.  There are biomarkers that have been studied for colon and pancreatic cancers extensively.

Then we get into the key issues of your body we look at the methyltransferase system.  This is one system people think of B vitamins: B-12, B-6, methylated folate that most people who are health conscious are taking.  The reason you’re doing that is to make sure you have methyltransferase.  Amyloid formation in the brain is also methyltransferase dependent, not just membrane.  The other component that causes abnormal amyloid is methyltransferase deficiency which is caused by homocysteine.  Same thing with phosphorylated Tau, neurofibrillary tangles in the brain, those are driven by methyltransferase issues in the brain. The definitive lecture series goes through each of these things in detail.  You can reduce your Tau tangle formation.  I explain how phosphorylated Tau works in the brain.  We measure methyltransferase, homocysteine, sphingomyelins and ceremide ratios.

54:42

We check mitochondrial health to make sure your mitochondria are tuned up.  These are all easily fixable.  If your mitochondria aren’t working properly, you can easily take carnitine and other supplements.

We check peroxisomal function which is where plasmalogens and DHA are made and helps regulate fasting triglyceride levels.  Everyone should have fasting triglycerides under 100.   If fasting triglycerides are over 100 something is not right, but it’s fixable.

We check cholesterol levels make sure your not cholesterol deficient.  Check HDL levels.

55:21

Then a couple other markers that are old school markers like creatinine.  People think of creatinine for kidney disease, but actually when you get older the biggest issue for people with low creatinine is you’re in a muscle wasting space.  Muscle wasting, sarcopenia, is a critical issue as we get older, but it’s also fixable. In the clinical trial, more powerful than the cognitive changes was the sarcopenia and muscle wasting.  We had dramatic improvements in muscularity in only four months.

We also check uric acid levels.  People think of uric acid for gout but low levels also indicate inflammation and other diseases.

The scan hits all the main areas.  We have certified doctors that understand it and there’s educational materials on the website for individuals.

For example, if cholesterol is 150, you ask why is the cholesterol so low.  You look up the chart and you see phosphocholine is at the 20% percentile, that’s the reason.  You can fix that with lecithin supplementation.  With choline levels up I can fix cholesterol levels.  If my fasting triglycerides are too high, I can fix that too, by increasing intermittent fasting level, ProdomeNeuro (supplement sold by Prodrome Sciences) will improve peroxisomal function, also moderate exercise with resistance training.

Just like your phone that you use all day, it expends energy so you put it on the charger at night.  Your car uses energy so you fill up the tank.  Your body does that every day, it switches from the fed state to the fasting state.  During the day you’re typically in the fed state, you’re up and active.  At night you’re on recharge and that’s when you’re in the fasting state. It’s in the fasting state that’s when you build.  It’s lipogenic.  During the day your body runs on glycolysis, it takes glucose/sugar that generates the energy but our rebuilding processes are shut down.  At nighttime, your body switches from glycolysis to lipolysis, which means it breaks down fatty acids from your fat cells.

58:21  Julie:  That’s when you’re in ketosis, at night.

58:24  Dr G:  Right.  The natural way for your body to get into ketosis is caloric restriction.  Typically, at night, you’re not eating so eventually you come into lyposis, you’re keto.  During the day your stomach digests food for energy.  At night your fat cells digest food for energy.  That’s when you’re building, that’s when you make your steroid hormones, your membranes, when you rebuild/fix all the stuff from during the day.  When you get older, we don’t consume as much energy during the day as we did when we were younger, it takes longer to get into that fasting state.  Late night snacking is especially really unhealthy because it prevents the body from getting into that fasting state and rebuilding.  You can do keto, but you should do both, your body is designed to switch back and forth.

59:31 Julie:  In our community, most of us do keto through fasting, exercise, we know healthy ways of getting into it, as well as our low carb diet.

This Prodrome Scan, everybody should get one, figure out what your plasmalogens are, get a snapshot of your health.  I’ve got two kits sitting in my kitchen, I can’t wait to do it.  Our show notes have a link on how to get the Prodrome Scan.

Also important, you’ve also created a plasmalogen precursor supplement that can essentially replenish plasmalogen levels.  We’ve identified that Alzheimer’s is a deficiency of plasmalogen. Tell us how we can increase our plasmalogen levels.

1:00:12  Dr G:  This is really exciting.  We’ve known about plasmalogens about 100 years now.  We know they’re obligate to human life.  If born with a genetic mutation that stops you from making plasmalogens either you will die in the womb or die before reaching your 10th birthday.  The consequences of plasmalogen deficiencies are severe.

The body has lots of plasmalogens, but it has different plasmalogens for different reasons.  Diseases like Multiple Sclerosis and ALS, those are white matter diseases.  The plasmalogen that’s in your white matter are protective, they’re the “plastic coating around the copper wire”.  They’re very impervious to oxidative stress.  That’s plasmalogens containing an Omega-9, like oleic acid from olive oil, but it has a plasmalogen backbone.  We have a product called ProdromeGlia which delivers 100% Omega-9 plasmalogens.  (The other product is called ProdromeNeuro).

1:01:25 Julie:  So how does someone know which supplement to buy?  Is it the result of their prodrome scan?

1:01:33 Dr G:  The simplest way is to know is ProdromeNeuro is for performance.  ProdromeNeuro has Omega-3 DHA in it, that’s critical for neuromuscular junction for muscularity and for cholinergic neurons in the brain.  The same neuron that handles cognition in the brain is the same neuron that handles muscle activity.  DHA plasmalogens are the ones that ApoEε4 carriers need, the DHA plasmalogens modulate the cholesterol efflux.  They also improve cognition in the synaptic cleft of neurotransmission.  Omega-3 DHA is a performance enhancing plasmalogen.  The omega-9 oleic acid is for protection, mostly for younger people: autism, multiple sclerosis, concussions, stroke.  You can use both the molecules will share each other.  As we get older, we typically need more of the DHA.  But they’re both extremely healthy for different reasons.

The problem with plasmalogens is the very last step in their manufacture is that they create what’s called a vinyl ether bond.  This is what gives it its special powers.  It’s packing power in the white matter protective sheath and it gives it its membrane fusion, neurotransmitter release, membrane modulation power for performance.  It’s also why it’s a very powerful antioxidant.  It neutralizes peroxides.  That process makes that molecule very sensitive to exposure in acidic environments.  So when you eat something that has plasmalogens in it, like a steak, when it hits the stomach acids, those plasmalogens break down.  Dietary sources of plasmalogens are very minimal compared to what we need.  We get insignificant levels from our diet.   As a chemist, I needed to design a molecule that can survive the stomach acids.  These are natural precursors, they’ve been around forever, they’re called alkyl-acylglycerols.  The problem with the natural sources is you can’t get them without other things, you can’t target specific neurons, you can’t get purified versions. What I’ve designed is purified alkyl-acylglycerols, two types, everything is 100% vegan, no risk of environmental contaminants in any of our products.  The DHA is from an algae source.  We make a free fatty acid form and put that on a plasmalogen backbone.

Your body needs lots of it.  The small dose is 900 mg.  Your body has grams.  You need to make sure you’re taking enough of it to have an effect.  I designed plasmalogen precursors that are 100% natural, they are part of the natural human biochemistry, so not only does it get absorbed in your blood, it elevates your overall blood plasmalogen levels, it’s designed to go into each of the cells of the body as a precursor.  This idea of the power grid vs your own capability, it does two things, it increases the entire grid of plasmalogens and every day you take a plasmalogen supplement it pulses itself into your neurons. It actually goes into every single cell of the body and lets the cell do the final two steps, they don’t even need to get plasmalogens from the blood supply anymore.  That’s what was interesting from the clinical trial, we didn’t segregate anyone for their baseline plasmalogen levels and we had the same clinical effect from those who had high plasmalogens at baseline vs people who had low plasmalogens.

1:06:29 Julie: Did you get baseline plasmalogen levels for the clinical trial?

1:06:40 Dr G:  Yes, it was a very controlled.

1:06:42 Julie:  Let me back up for a second.  So Dr Goodenowe just presented at the Alzheimer’s Association International Conference (Jul 26, 2021 – Jul 30, 2021).  This is not published.

1:07:04 Dr G:  Yes, this is what we presented in Denver.  This was a clinical trial approved and financed by the Alzheimer’s Association. The Alzheimer’s Association paid for this.

1:07:14 Julie:  That’s very encouraging.

1:07:19 Dr G:  We did it in collaboration with a group in Santa Monica, Dr Sheldon Jordon, neurologist.  We did a very simple, straightforward, open label.  The goal was to know how much plasmalogen precursor we needed and what was the effect of adding plasmalogens to blood levels.  We had a hodge-podge of individuals.  We had 22 people, all had cognitive impairment, a clinical dementia rating scale (CDRS) of 0.5, 1.0, or 2.0.  There are four scales on that rating scale:  0.5 is mild cognitive impairment, 1.0 is moderate, 2.0 is semi-severe, and 3.0 is very severe.  Fourteen had mild cognitive impairment.  Four had a CDR of 1.0, and four had a CDR of 2.0.  Everyone had cognitive impairment, there was no control.  We had as young as 37, some had Lewy Body Disease, most had Alzheimer’s dementia.  Dementia comes in many flavors, we have vascular dementia, Alzheimer’s dementia, Frontotemporal lobe dementia, Lewy Body dementia.  Dementia is reduced cognitive function but there are different types of cognition.  We did no selection, this was a random group of people.

We got blood baseline levels. Cognition at baseline.  Looked at their mobility, a 30 second sit-stand which is stand and sit as many times as can in 30 seconds, it’s a measure of mobility and muscle strength.  That was done every month.  So we had a baseline.  In the first month, they took 1 ml a day of the ProdromeNeuro, or one bottle lasting one month.  At the end of the first month they were tested cognitively, mobility, and blood samples drawn.  Then they went home with two bottles of ProdromeNeuro, so they doubled the dose, 2 ml a day.  We did that for two months.  At the end of the second month we tested cognitively, mobility, and blood samples drawn.  Then we gave them 4 bottles of ProdromeNeuro, one bottle a week, 4 ml a day.  That’s the dose from animal trials for complete neuro protection for neurodegeneration.

We have a number of people who are on the high dose that have had dramatic improvements in Parkinson’s and Alzheimer’s.  We had people with a CDR of 3.0 who are down to 1.0 now since they’ve been on the high doses of the Plasmalogens.

1:10:53 Julie:  Wow

1:10:55 Dr G:  Then we did a wash out phase for a month and took tests at the end.  So four people had a CDR of 2.0, which is the most severe of the people in this trial, three of those four improved by more than an entire CDR score, they went from a 2.0 to a 1.0 or a 0.5, a dramatic improvement.   Half of the people with a CDR of 1.0 improved.  Remember, Alzheimer’s is a disease you’re not supposed to improve from.  When you do a clinical trial what you’re doing is trying to do is ask the question, “can we reduce the rate of decline” no one ever talks about improvement.

1:11:43 Julie:  Absolutely.

1:11:55  Dr G:  I know Dr Dale Bredesen talks about improving.  There are others out there who are not satisfied with just reducing decline, we can get better.   We had significant cognitive improvement in individuals.  The other thing that was the mobility improvements were quite dramatic, 4-5 increased sit-stand, so the sit-stand improvement was actually more robust than the cognitive improvement.

1:12:29 Julie:  Wow

1:12:30  Dr G:  From my own experience it is muscle enhancing, it improves your exercise capability.

1:12:43 Julie:  At what dose did you see the most improvement?  4 ml?

1:12:50  Dr G:  About 2 ml is probably where most people will be.  For some of the severe people, the 4 ml helped.  Remember these are people who already have cognitive impairment, the blood test is designed to understand biochemical health.  If you have a neurological disease, if you have symptomology, then biochemically you want to supplement in an appropriate way for that disorder regardless of the blood test.  The blood test is designed to make sure there’s no boogey man under the bed that you don’t know about.

1:13:38 Julie:  That’s actually very encouraging because that’s a step some people could skip if budget is tight, skip the Prodrome Scan and go directly to the supplement.

1:13:50  Dr G:  I’m going to create a Breaking Alzheimer’s package that I’ll be coming out with later.  Because the other thing with Alzheimer’s and supplementation is it becomes pretty complicated.  It’s hard for us to send 10 bottles of supplements out to people.  We’ll be packaging things in a much better way.  There will be a designed supplement biochemically engineered package for people.

1:14:26 Julie:  When you went to the washout period, did people lose the gains they incurred?

1:14:36 Dr G:  The plasmalogen levels came down. The gains stayed for most people.  We had a couple people that within two weeks, these were the more severe cases, they opted not to complete the trial, they started to dose again. It’s individual dependent.  Symptomatically, the plasmalogens have actual physiological effect in improving cognition.  Anyone who takes the supplement will typically experience that, feel a sense of awareness.

1:15:17 Julie:  My understanding is the people need to take the supplement for life.

1:15:23 Dr G:  Pretty much.  It’s kind of like a Vitamin D story, there are natural ways to increase Vitamin D, plasmalogens are the same, there are lifestyle practices that improves it, like fasting, exercise.  When you get in your 60s, 70s, 80s and 90s you’re not dealing with what happened last year, you’re dealing with what happened for 30 years.  You can’t fix 30 years of decline in 2 weeks.  If you want to push time back, you have to create the biochemical reserve, that will take a while.  It’s like a game of musical chairs, we want our players around the chairs so we have our guy ready to sit in the empty chair. Biochemical reserve capacity has excess plasmalogens available.  The brain has a slow rate of turnover, for us to restore neuronal membrane structure it takes time.  So yes, it’s something you will want for the rest of your life for prevention and optimal health.

1:17:02 Julie:  This is so incredibly exciting.  When are you going to publish the results of the trial?

1:17:09 Dr G:  We’ll write it up pretty soon.  I put a video together on the results.

The other thing we measured was antioxidant biomarkers, this was the second part of the trial. We measured malondialdehyde, these are aldehyde levels, we measured catalase function, we also measured superoxide dismutase levels.  We had a very powerful correlation, really exciting to me, hopefully to readers as well.  When you get oxidative stress there’s many mechanisms.  The first phase is this super oxide radical is formed that normally gets neutralized by an enzyme called super oxide dismutase (SOD). When that gets mutated we have diseases such as ALS.  That takes the super oxide radical and converts it to hydrogen peroxide, which is less damaging than the super oxide radical but still not good.  Then this hydrogen peroxide gets neutralized either by glutathione peroxidases, catalase, or plasmalogens.  But if that doesn’t happen those peroxides will eventually oxidize lipid membranes, you get peroxidated lipids, that’s the nasty stuff that causes inflammation, vascular disease and so on.  Malondialdehyde (MDA) is a more sensitive biomarker.  C-reactive protein is a biomarker for oxidative stress, but malondialdehyde is much more specific.  We had a very powerful correlation, P value of 10-7 in a small trial, crazy.

1:18:46 Julie: Wow

1:18:47  Dr G:  We looked at people with high MDA levels vs low MDA levels, and everyone who had high MDA levels the plasmalogens neutralized them.  We neutralized the aldehyde levels so oxidative stress levels really went down.  Catalase is an enzyme, it’s a protein it works to neutralize hydrogen peroxide. When we reduced peroxide load with the plasmalogens, catalase levels started recovering.  We also had improvements in SOD.  Very powerful mechanistic data.  Our average plasmalogen levels doubled and more, a dose dependent effect.

That video is live now, that data is available.

1:19:47 Julie:  Fabulous.  This is astounding news.

1:19:58 Dr G:  The first time in human history we’ve been able to target and elevate blood plasmalogens.

1:20:09 Julie:  How was your presentation received?  I’ve been following the news out of the AAIC and I’ve been disappointed they’re not reporting on this.

1:20:34  Dr G:  I’m disappointed but it’s a tough world out there, these institutions need to live, they’re funded by donations, their ability to get things done.  They’re between a rock and a hard place.  They funded this trial, so they’re doing this kind of work, the challenge is in the delivery mechanisms.   What do you do with a trial like this afterward?  The pharmaceutical industry has a very simple delivery mechanism.  They get the FDA approval, pharmacy delivers, doctor can prescribe, it can get distributed very quickly.  The Alzheimer’s Association has to be an open tent for all people.  They do a lot of epidemiological studies, they do nutritional studies.  The problem with the nutritional work and the stuff we do, as exciting as it is, is that we need to solve the delivery problem.  How do we get it to everybody?  That’s my biggest focus.

1:21:53 Julie:  You have an educational hurdle.  You need to explain to people all about plasmalogen levels.  Doctors aren’t getting this.

1:22:07 Dr G:  No, but they’re getting there.  Our network of doctors is growing dramatically.  In the end the proof is whether it works or not. Doctors are really excited because they’re seeing dramatic results in their patients.  The anecdotes we get from patients and their loved ones.  One of the biggest problems we’ve had to break down is people don’t expect health anymore. They expect to live with disease.  We’ve convinced people they can’t recover from disease.

1:22:49 Julie: There needs to be a paradigm shift.

1:22:52 Dr G:  People have to realize you shouldn’t be sick.  The human body is designed to work.  If it’s not working, it’s not balanced properly.  That’s what we do with biochemical engineering, we deal with very simple, straightforward biochemical stuff.  You can measure it, before and after, you can fix it.  It will become mainstream, we are in the beginning of a major shift.  The pharmaceutical industry is imploding.  This new Alzheimer’s drug, $35,000 a year for amyloid lowering.

1:23:42  Julie:  It’s actually more than that, $56,000.

1:23:46  Dr G:  It’s crazy and it doesn’t even work. Actually, the drug works perfectly.  What it’s designed to do is to lower amyloid and it absolutely does that.  It does exactly what it supposed to do.  Just like statins, statins work, cholesterol levels will go down, the question is whether that’s useful or not. Pharmacologically the drugs do exactly what they’re designed to do, the question is if what they’re designed to do have any positive health consequences.

1:24:31  Julie: They have nine years to gather more evidence, so we’ll see.

1:24:41  Dr G:  There are many scientists out there and it takes years to get government grants.  Changing trajectories in public research is not trivial and it’s very competitive.  They get one little advancement at a time.  You can’t suddenly switch gears when you have thousands of scientists studying tau and amyloid and esoteric proteins.  It takes a while.

1:25:28 Julie:  You’ve got a great attitude.  I’ve been in this space about nine years now and what you’ve accomplished is nothing short of amazing and I’m so excited to share that.  I feel badly we’ve taken so much time.  I want to thank you so much for sharing your work.  We’ll share links in the show notes.

1:26:16  Dr G:  The APOEε4 lecture series especially, it gets to the root of the matter.

1:26:22 Julie:  I have one last question, where can people get a copy of your book.

1:26:26 Dr G:  You can go to Prodrome.com, it’s also on Amazon.

1:26:35  Julie:  Wonderful.  Breaking Alzheimer’s, I love the title.   I can’t thank you enough for sharing your time and your work.

Subscriptions are available on many platforms including

Dr. Dayan Goodenowe joins Julie Gregory to discuss his research into disease states identified by metabolomic testing. They focus particularly on neurological health. He explains what goes wrong biochemically as dementia develops and highlights age-related diminishing plasmalogen levels as a major driver of disease. He describes his research showing that ApoE4 carriers require more plasmalogens to maintain cognition, and he identifies diet and lifestyle measures that support plasmalogen levels. Finally, they discuss Dr. Goodenowe’s newly available ProdromeNeuro dietary supplement and the evidence showing its effect on plasmalogen levels in the body.

Podcast Part 2: Plasmalogens & Neurological Health

Educational Seminars: free registration

Prodrome Sciences: supplements and tests

Breaking Alzheimer’s book: direct / Amazon

More info: DrGoodenowe.com

For pre-publication discussions of clinical trial results sponsored by the Alzheimer’s Association and presented at the Alzheimer’s Association International Conference (AAIC) in July 2021, watch episodes C105 and C106 at Dr. Goodenowe’s Educational Seminars site after free registration.

0:30 Julie – Welcome to Dr Dayan Goodenowe, founder and CEO of Prodrome Sciences.  In 1999 he invented a technology platform that’s been used to analyze thousands of human samples around the world.  Through collaboration with international researchers and doctors, Dr Goodenowe is an expert on the biochemical basis of neurological diseases, including Alzheimer’s, Parkinson’s, Multiple Sclerosis, autism, bipolar disorder, and schizophrenia.  He is an inventor of numerous patents, an author of numerous scientific publications, and an international speaker. He is passionate about demystifying science for accessibility to everyone. Dr Goodenowe has developed blood tests and dietary supplements designed for individualized health optimization which he believes is the key to disease prevention and longevity.   Dr Goodenowe has been working with ApoE4 community for about 2 years now.

3:12 Dr G – The ApoE4 community is unique with some members who are very well informed, similar to other communities with genetic or special needs.  The scientific community is conservative, but individuals of a specific community can become experts at their own disorder/issue, more so than the scientists because they can follow different rules.  

7:08 Julie – It is also a good thing when researchers recognize the importance of partnering with patients to find our own cure.  We have skin in the game. We’re trying to save our own lives. N=1 rules. 

7:51 Dr G on his background –  Chemistry and biochemistry, then further into neurochemistry and psychiatric disease in terms of the neurobiology and the neurochemistry of the brain.  Also agriculture as a farm boy from Canada.  A synthetic and organic chemist.  

8:27 Dr G – There are three main levels of organization: biology, chemistry, and physics.  

9:59 Dr G –  From a human perspective everything comes down to chemistry.  Chemistry is what we have most control and power over.  

10:58 Dr G –  We are fundamentally biochemical reactors.  We convert carbohydrates, proteins, and fats into small molecules, and those small molecules get circulated through the body and they keep us alive.  For a great period of our life, this works very well. We have a good prototype for what good health is.  

12:23 Dr G – All organisms have a genotype, that genotype drives structure and all the proteins in the body come from the genome.  Our organizational structure can be broken into three categories:  

13:36 Dr G – The genome is like the city planning map, it gives limits of what the city can achieve. One can look at a map and see traffic problem areas, where the constraints are, based on the structure, not even looking at the cars on the roads. 

14:30 Dr G – The proteins (proteome) are like the actual roads. For example, other genomes have 6 lane freeways for carrying cholesterol, but ApoE4s have 3 lane freeways for carrying cholesterol, which at 3 o’clock in the morning is fine, but at rush hour is inadequate.  

15:36 Dr G – Small molecule chemistry, i.e. metabolomics, is measuring the cars on the road, which is unrelated to the genome or proteome.  By measuring the actual activity we see what is really happening. At 3 o’clock in the morning, we have complete functionality, the predisposition of a constrained freeway isn’t a problem at that hour.  However, at rush hour this changes, metabolomics measures that. During rush hour, ApoE4s have cars on side streets where they shouldn’t be. Upon such an observation, one can work back as to why something happens, that’s what metabolomics does, and we can work to optimize our biochemistry. 

18:30 Julie – So you think the reduced cholesterol transport is our biggest issue?

18:38 Dr G – It is the biochemical mechanism of the ApoE4 protein. It can cascade into other systems, but that is fundamentally the core biochemical difference.  That may translate into different things.  

19:20 Dr G – As with all genetic predispositions, it’s a matter of identifying what your predispositions are or what your optimal space is, and upon finding your optimal space, keeping it there.  

19:30  Julie –  Metabolomic testing gives us a snapshot of our current state of functioning to manage our health.  Talk about plasmalogens and ApoE4.

20:08  Dr G – With genetics we can sequence the genome and the basis of the genome translates into proteins.  So when the proteomics of the ApoE4 genotype is measured it can be mapped it back to the genome.  Metabolites are not genome dependent.  In order to make headway with the biochemistry, I had to find a way to measure thousands and thousands of small molecules simultaneously.  That was the core technology that I invented, called non targeted metabolomics. This allows taking a blood sample or any biological sample and measure thousands of small molecules under different conditions.  When implemented in clinical trials around the world what kept coming up in the cognitive studies and Alzheimer’s studies was that plasmalogens were lower in those with cognitive impairment.   The lower the plasmalogen level, the more severe the cognitive impairment. The association was powerful. The original association with plasmalogen was with cognition, but then it became clear it was also associated with other neurological disorders:  stroke, Parkinson’s, ALS, schizophrenia, bipolar disease.  

23:02  Julie –  Plasmalogens are also correlated with lower overall mortality

23:09 Dr G –Yes, but we need to be careful, the tendency is when we find one association we get obsessed.   

24:23 Dr G  – Plasmalogen is a critical component of neuromembranes.  It has three critical functions that work together or in isolation depending on the individual.  One is membranes of the whole body. The human body is made up of trillions of cells. These cells are 3 dimensional, like a building with walls, without the cellular structure we’d just be soup.  What defines the cells of the body is the phospholipid bilayer, the lipids that make up the structure of the cell walls. There are the organelles inside the cells, like mitochondria and peroxisomes, and they have membranes around them too.  As membranes become stiff or more restrictive, the proteins that work in those membranes have to change their biological activity. When they change their biological activity, they compensate. That’s what’s happening in ApoE4s in terms of amyloid.  The impaired ability for ApoE4 to export cholesterol out of membranes ends up with an excess cholesterol composition within the membranes and that increased cholesterol causes the membranes to be stiffer. When they’re stiffer, the enzymes that process amyloid, the amyloid precursor protein, shifts the equilibrium to the bad protein which is the beta-secretase from the good protein which is the alpha-secretase.  So when you shift to more beta, you get amyloid formation. Since ApoE4s have a predisposition to reduced cholesterol clearance, then there’s a predisposition for increased amyloid. The amyloid is a biomarker of impaired membrane structure which leads to impaired neurological function.  

28:10 Dr G  – So of the three things, one is that the plasmalogens are critical for membranes:  membrane fluidity and membrane structure and function.  

28:19 Dr G – The second one, which is why the association with cognition, is that plasmalogens are also involved in a specific membrane function, the vesicular release of neurotransmitters.  Our neurons are a biochemical circuit board, in order for signals to pass from one neuron to another neuron, the communication is biochemical, they have to be released into the synaptic cleft and the release of neurotransmitters is dependent on plasmalogen composition.  

29:19 Dr G – The third is that plasmalogens are very powerful antioxidants and free radical scavengers.  By orders of magnitude they scavenge more free radicals and oxidative stress than all other antioxidants in the body combined.  We make a lot of plasmalogens, it’s about 20% of the brain, we have high concentrations in the heart, lungs, kidneys, retina. In addition to making a lot, we use a lot.  It is designed to protect other molecules. Ordinarily, we have the ability to make a lot of them, but over time, and with other diseases, at some point our ability to make plasmalogens can become less than what we need.  Once that is out of balance, the plasmalogens deplete.   

31:25 Julie – Tell us about plasmalogens in the ApoE genotype, ApoE2s have high plasmalogens versus ApoE4s have lowest levels of plasmalogens?

31:57 Dr G – There is no association between ApoE genotype and plasmalogen levels.  The association is that the risk of dementia is dependent on the plasmalogen level.   An ApoE4 carrier with high plasmalogens does not have increased risk of dementia, the high plasmalogens are protective.  It’s the level of plasmalogens that’s required for that protection which is dependent on the genotype. So if a person is an ApoE3 carrier, the level needed for protection is, strictly for illustration, say 50.  If the individual is an ApoE4 carrier that level might be 80 and if an ApoE2 carrier it might be 30. The key point is how many plasmalogens you need is dependent on your genotype. An ApoE4 carrier needs higher levels of plasmalogens than an ApoE2 carrier. 

34:14 Julie – An ApoE4 homozygote (ApoE4/4) might need even more plasmalogen?

34:19 Dr G – Exactly

34:20  Julie – Your metabolomic testing can show us what our plasmalogen levels are, what about surrogate biomarkers?  

34:38  Dr G – Plasmalogens are made in the peroxisomes of our body.  If you have high HDL and low triglyceride levels, that’s usually an indicator of good plasmalogen levels.  The plasmalogens are transported on HDL particles in the body. There’s a correlation, those with high plasmalogens have high HDL.  I typically ignore LDL. Folks with good peroxisomal function have higher levels of both HDL and LDL. Cholesterol is made from molecules in the peroxisome.   People who have good functioning peroxisomes will have naturally higher levels of cholesterol, usually the good cholesterol, HDL. Peroxisomes also consume triglycerides.  The essential fatty acids, DHA and EPA, act as peroxisome stimulators and one of the outcomes is reduced triglyceride levels.  When someone has high triglyceride levels it usually means someone has reduced peroxisomal function. You can infer that if you can get fasting triglyceride levels low naturally, not through drug use, you will aid peroxisomal function.  Artificial changes in certain biomarkers don’t actually change the underlying function, the drugs just change the results of the biomarker test. If diet and lifestyle results in naturally low triglycerides and naturally high HDL, you can infer that you are optimizing plasmalogen levels.  Also resistance training can build plasmalogen levels.  

38:04 Julie – Resistance not aerobic? 

38:09 Dr G –  Absolutely, especially in the elderly.  There’s a balancing act. We’ve seen anecdotal evidence of low plasmalogen levels in super athletes.  You can overdo it, positive effects of the exercise are offset by the negative effects. Exercise does create oxidative stress. You want a balanced exercise routine, especially in the elderly, where you’re stimulating the growth and biochemistry of the muscles, but not overdoing it.  The other part is a low inflammatory diet to reduce the body’s consumption of plasmalogens. So you want to increase plasmalogen production by increasing peroxisomal function and you want to decrease the consumption of plasmalogens by making sure your body has other anti-inflammatory antioxidant capacity to help carry the weight of the plasmalogens.  

39:33 Julie – Can you describe a diet that would promote healthy plasmalogen levels?

39:43 Dr G – Before designing and manufacturing a supplement, I had my dad on such a diet.  He has plasmalogens in the 85th to 90th percentile and he’s in his 80s.  He has higher functionality now than 20 years ago.  His routine: moderate resistance training 3 – 4 times a week, and stimulating peroxisomal function with Omega-3, mostly DHA, supplementation, and then reducing oxidative stress through natural supplements like Coenzyme Q10, acetylcysteine, and acetylcarnitine. No overdosing of those, just enough.  We know you can’t overdose plasmalogens.  

42:00 Julie – Was there a specific diet that you had your dad on?

42:11 Dr G –  Just the basic ingredients, we’re farm boys, basic meat and potatoes diet, eggs and vegetables too, trying to keep the processed carbohydrates down.  Basically a mini-paleo, balanced diet. 

42:45 Julie – The meat and eggs are good sources of choline which is very important.  

42:48 Dr G – That’s one of the main deficiencies we find in people.  Even people that have a diet that looks like it has enough choline can still be choline deficient.  Choline supplementation or ethanolamine supplementation, we need both of these in our diet. You can’t make ethanolamine, you have to get it in your diet, choline we can make, but the energy needed to make choline is quite high.  We’re learning more about supplementation in the longevity space. My thinking has moved from disease focus to optimized function focus. We’re preprogrammed to look at the bad and to try to fix the bad, we think of everything as a disease.  We’re moving away from this disease focus.

44:53 Julie – That’s what your testing allows us to do.  It allows us to intervene in that prodromal period. Tell us about the supplement you created.   

45:26 Dr G – So with plasmalogens, we saw this powerful correlation with neurological disease, especially Alzheimer’s and cognition.  So the next step was to ask how do we get more of them? In theory we should be able to eat them.  

46:18 Julie –  There are clinicians who recommend that, they recommend ApoE4s eat lots of shellfish because they’re high in plasmalogens.  Does that work? 

46:30 Dr G – It does to a certain degree.  The reality is this vinyl-ether bond of plasmalogen has a special quality that gives it its very potent antioxidant and free radical scavenging capabilities but the downside is when exposed to acid it gets broken down to an aldehyde.  If you consume high levels of plasmalogen in your diet, you’re generating toxic aldehydes, because the stomach acids will convert the vinyl-ether bond, which is why we can’t absorb much through diet. Some plasmalogens have the ether bond, not the vinyl-ether bond, and those plasmalogens make it through the food supply, but that’s not the majority.  So from a chemistry perspective, we had to design a molecule that would survive the gut. It’s bioidentical, but instead of the vinyl-ether bond it has the ether bond so that it’s stable in the gut. Also, not all plasmalogens are the same, we want the Omega-3 plasmalogens, we want the DHA plasmalogen. It’s the phospholipid DHA that’s important, but you can’t get phospholipid DHA from the diet. 

48:32 Julie – Dr Rhonda Patrick a theory that DHA in phospholipid form is preferential for ApoE4 carriers to get DHA to the brain, she recommends salmon roe caviar.

48:54 Dr G – Nothing in the body is completely absolute, but we’re designed to eat animals and plants and convert that in to what the body can use.  Our digestive tract has a number of enzymes and processes to ensure just the critical components enter our system. On triglycerides, fats are triglycerides meaning they have a glycerol backbone with three fatty acids.  Triglycerides don’t get absorbed into the body, they need to get processed first.  First one fatty acid at the sn-1 position is taken off, then the second fatty acid at the sn-3 position is taken off, leaving a monoacylglyceride which is what is absorbed into the bloodstream to circulate in the body.  The liver puts the fatty acids back on to send to the adipose tissue. The triglycerides in an Omega-3 fish oil supplement is going to have DHA on a triglyceride backbone, but the triglyceride doesn’t go in the body, the monoacylglyceride does.   

51:05 Dr G – Phospholipids are metabolized differently.  When you eat phospholipids from the food supply the phospholipase cleaves off the sn-2 position which is where the DHA is, the fatty acid that you want.  You absorb what is called a lysophospholipid, it doesn’t contain DHA. Generally, we’re not getting DHA phospholipid from the food supply. 

51:55 Dr G – We want to get the DHA Omega-3 on the plasmalogen phospholipid in the blood stream.  So we designed a molecule to do that. It is metabolically engineered based on human biochemistry.  The molecule we designed for a supplement is an alkylglycerol, it’s like a triglyceride only it has the plasmalogen bond at the sn-1 position which is stable in the gut.  

52:35 Dr G – The second big difference is we put the DHA molecule at the sn-2 position.  Unlike a triglyceride where a monoacylglycerol is being absorbed, in a triglyceride the sn-1 and sn-3 positions are the same.  But in a plasmalogen glyceride, as in my plasmalogen supplement, the sn-1 position has the ether bond. This means instead of a monoacylglycerol being absorbed in the blood, the DHA at the sn-2 position is absorbed.  That gets directly converted into a phospholipid and that DHA is conserved through the biochemistry of the body.  

53:25 Julie – Have you tested humans with your supplement to see if their plasmalogen levels are increasing? 

53:35 Dr G – Yes.  We can double plasmalogen levels in 24 hours.  We have measured several people. Six of us did a formal trial and we doubled our plasmalogen levels of the target, DHA.  The plasmalogen supplement is a high concentration of Omega-3s, DHA, and a little EPA and that converts directly into DHA plasmalogen.

54:26 Julie – How much did you have to take? 

54:28 Dr G – We took a higher dose, we took 100 mg per kilogram which was about 10 mils.  We sell the bottle as a 30 mil bottle, a month’s supply, so our dose worked out to be about a third of a bottle.  

54:45 Julie – You’re a brave man.

54:47 Dr G – It’s just oil, not a big deal.

54:50 Julie – I say that because I’ve tasted it. 

54:55 Dr G – It does taste horrible. 

55:03 Julie – I think the taste is improving, is that my imagination? 

55:07 Dr G – It’s not your imagination.  The next batch you’ll love. We just went to a 100% vegan supply.  The problem is there’s no efficient way of chemically making DHA, so we rely on food sources.  The classic source is from fish products. We’ve been able to source a high purity algae source.  The next round of product should have zero fish taste or smell and have a little bit higher DHA concentration.

56:50 Julie – We mentioned before we’ve been working together allowing our members to use your metabolomic testing.  We hope to make an announcement in the near future as well as incentivized pricing and packaging. We’re also using a software platform to capture data points.  We want to help members of our community do self-directed research. Members could get a baseline, use the plasmalogen supplement for a couple months and then retest for results. 

57:45 Dr G – We’re a huge supporter of N of 1 work.  We believe ultimately human health will benefit from average users sharing their experiences, systematically improving their biochemistry.  You can’t fix what you don’t know. You need to know what to fix before you get sick. Let’s not wait for disease to occur.  

58:42 Julie – For listeners who want to get the metabolomic testing and supplement right away, go to this Dr Goodenowe’s website, prodromesciences.com.   If an ApoE4 carrier, when you place your order, please note that you want to join our group project once it’s launched, we think we’re close to launching.  

59:40 Dr G – I want to demystify biochemistry, people should feel they have the power to do this.  If you get the biofeedback as well as a visceral feeling of feeling better, this gives a sense of empowerment.  Changing diet and behavior is hard work. People need positive feedback, it’s hard to maintain positive behavior.  People have the power to control a lot of variables. If you get the biochemical feedback early on, it helps a person to maintain a program.  Sometimes the physical symptomatic observation lag behind the biochemical changes.  

1:02:06 Julie – I am part of a small group who got to try your supplement, I was surprised at the number of people who felt almost an immediate difference.  

1:02:25 Dr G – We’ve got trials going on around the world right now.  In people with cognitive impairment, 100% of their caregivers are saying they’re seeing improvement in engagement, awareness, interaction, and cognition. 

1:03:22 Dr G – With Alzheimer’s the idea of improvement is “out there”.  Currently the approach is to reduce the rate of decline, no one talks about improving function.  What we’re seeing is improved function, and what we want is to improve and sustain.  

1:04:38 That’s what our community is trying to do.  We see anecdotal, N of 1 evidence all the time.  People change their lifestyle, diet, and take targeted supplements, they feel better, they feel cognitively sharper.  It’s not a clinical trial, but we see it in hundreds and hundreds of our members. We’re with you, we believe cognition is much more fluid than researchers lead us to believe and it’s based directly on lifestyle factors which we have control over and metabolomics testing will allow us to measure.

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Dr. Terry Wahls joins Julie Gregory to share her personal story of triumph over secondary progressive multiple sclerosis using a diet and lifestyle regimen guided by paleo principles. She discusses the overlap between multiple sclerosis and ApoE4 and shares specific strategies that can help ApoE4 carriers mitigate their risk of neurodegenerative disease. Additionally, Dr. Wahls shares her latest research, how her protocol has changed, and provides an overview of her new book, The Revised, Expanded Wahls Protocol: A Radical New Way to Treat All Autoimmune Conditions, available now.

New book: The Revised, Expanded Wahls Protocol: A Radical New Way to Treat All Autoimmune Conditions

TEDx Talk: Minding Your Mitochondria

Website: terrywahls.com

Research and published papers

Supporting articles

Facebook

Twitter and especially Eat This Every Day

Previous books:

The Wahls Protocol: A Radical New Way to Treat All Chronic Autoimmune Conditions Using Paleo Principles (2014)

2:27 – Dr. Wahls tells her story, how she went from a conventional medicine doctor skeptical of special diets and supplements to where she is now: a functional medicine doctor dedicated to research and teaching others on the importance of food to heal. The transformation occurred as result of being diagnosed with progressive Multiple Sclerosis (MS) which put her in a tilt recline wheelchair for four years. Today she rides her bike to work.

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