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Dr. Perlmutter’s groundbreaking new book, Brain Defenders, is now available for pre-order. Discover how to protect your brain and future health - reserve your copy today at https://www.braindefenders.com.

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On this episode of The Empowering Neurologist, I’m joined by Dr. Sarah Marzi, a neuroscientist at King’s College London and a principal investigator at the UK Dementia Research Institute, whose work is transforming how we understand neurodegenerative disease risk.

Dr. Marzi’s research focuses on gene regulation in the human brain, particularly within microglia, the immune cells that orchestrate inflammation, synaptic pruning, and repair. Her studies show that genetic risk for diseases like Alzheimer’s is concentrated not in protein-coding genes, but in regulatory regions of the genome, epigenetic switches that control immune behavior in the brain.

This conversation with Dr. Marzi is not just about disease. It’s about agency. Understanding epigenetics helps explain how lifestyle, environment, and immune balance can influence brain destiny. It’s science that empowers prevention, resilience, and hope.

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00:00 Intro

03:12 Epigenetics and Neurodegenerative Disease

04:49 Why Alzheimer’s Is Not a Single Gene Disorder

09:18 Protein Aggregation and Brain Cleanup Failure

10:55 Microglia vs Neurons in Alzheimer’s

19:04 Blood Brain Barrier and Inflammatory Signaling

20:39 ApoE Genetics Explained

23:37 Human Microglia Transplanted Into Mouse Brain

30:02 Vitamin D Receptor and Protective Gene Programs

38:18 Environmental Toxins and Parkinson’s

44:59 C1q Activation and Synapse Loss

49:33 Why Substantia Nigra Is Uniquely Vulnerable

51:39 Paraquat, Mitochondria and Converging Toxic Pathways

53:00 Epigenetic Memory of Toxic Exposure

54:09 Histones and Gene Regulation in Alzheimer’s

57:41 Oligodendrocytes as a Hidden Player

59:32 Why Single Target Drugs May Fail

01:02:10 Detecting Disease Through Blood and Machine Learning

01:04:41 Can Lifestyle Modify Epigenetics

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Dr Sarah Marzi is a Senior Lecturer in Neuroscience at King’s College London and a Group Leader at the UK Dementia Research Institute. Her work focuses on how our genes and environment change cellular processes in the brain and can predispose us to neurodegenerative diseases such as Alzheimer’s, Parkinson’s and motor neuron disease.

An expert in epigenetics – the chemical switches that turn genes on and off – Dr Marzi uses cuttingedge genomic techniques on human brain tissue as well as cell and animal models. Her team combines these experiments with advanced statistics, bioinformatics and AI to map the earliest molecular changes that make brain cells vulnerable to disease, particularly in immune cells of the brain called microglia. This work aims to reveal how both genetic variants and environmental exposures, including pesticides, contribute to disease risk and to uncover new avenues for therapy.

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