Jack’s Podcast on Slowing Aging

Will Alzheimer be helped by Mitochondrial Biogenesis

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This briefing document summarizes the key themes and findings presented in the provided review article on Alzheimer's disease (AD). The article, published in the European Journal of Neurology in 2018, offers a comprehensive overview of AD, including its epidemiology, genetics, pathogenesis, pathology, clinical presentation, diagnosis, and treatment strategies, while also looking ahead to future research directions.

Key Facts and Ideas:

  • Global Health Concern: Alzheimer's disease is a growing global health concern with "huge implications for individuals and society." (p. 59) It is the "most common cause of dementia," which is defined as "acquired progressive cognitive impairment sufficient to impact on activities of daily living." (p. 59) Current estimates suggest that "44 million people live with dementia worldwide at present." (p. 59)
  • Increasing Prevalence and Cost: The prevalence of dementia is expected to rise significantly in coming years, particularly in Western countries where it is the single biggest cause of disability. The estimated cost of dementia in the US alone "may exceed US$600 billion [2]." (p. 59)
  • Epidemiology and Risk Factors: While the exact causes are complex, AD is influenced by a combination of genetic and environmental factors. "Typical' late onset AD is likely to be driven by a complex interplay between genetic and environmental factors." (p. 59) "Epidemiological evidence suggests education and physical exercise may protect against AD, whereas mid-life hypertension and diabetes adversely influence risk [1]." (p. 60)
  • Genetics: Genetic factors play a significant role in AD, particularly in the less common early-onset familial forms. "Whilst the vast majority of AD occurs on an apparently sporadic basis, mutations in three genes – amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) – cause a rare (<0.5%) familial form of AD (FAD)." (p. 59) The APOE gene is identified as a "single biggest genetic risk for sporadic AD." (p. 59)
  • Pathology: The hallmark pathological features of AD are the accumulation of amyloid plaques and neurofibrillary tangles in the brain. "The cardinal features of Alzheimer pathology are amyloid plaques and neurofibrillary tangles (NFTs)." (p. 60) Amyloid plaques are composed of aggregates of the β-amyloid (Aβ) peptide, while neurofibrillary tangles are composed of hyperphosphorylated tau protein. Other pathological processes include "neuronal loss and synaptic dysfunction." (p. 60)
  • Pathogenesis (Amyloid Hypothesis): The article discusses the prevailing "amyloid hypothesis," which proposes that the accumulation and oligomerization of Aβ is a primary driver of the disease process, leading to synaptic dysfunction, tau pathology, and neuronal death. "The amyloid hypothesis, the prevalent theory of AD pathogenesis, suggests that accumulation of pathological forms of Aβ produced by sequential cleavage of the APP by the β- and γ-secretases initiates the primary pathological process, driving through an imbalance between Aβ production and Aβ clearance." (p. 61)
  • Clinical Features: The most common presentation of AD is with "insidious progressive problems centered on episodic memory." (p. 63) As the disease progresses, individuals experience difficulties with "multi-tasking and loss of condition." (p. 63) Behavioral changes, including depression and apathy, are also common.
  • Diagnostic Approach: The diagnosis of AD is primarily clinical, based on a detailed history and neurological examination. Cognitive assessments are crucial. While the definitive diagnosis still relies on neuropathological examination post-mortem, "recent diagnostic criteria from both the National Institute on Aging (NIA) and the International Working Group (IWG-2) now incorporate early (amyloid) and late (tau) biomarkers to improve diagnostic sensitivity and specificity." (p. 63) Neuroimaging (MRI and PET) and CSF analysis play an increasing role in supporting the diagnosis and identifying biomarkers.
  • Biomarkers: Biomarkers, including those measured in CSF (Aβ and tau) and through PET imaging (amyloid and tau), are becoming increasingly important for earlier and more accurate diagnosis, particularly in the preclinical and prodromal stages. "Tau PET imaging, using tracers such as AV1451, is a recent development which is currently only used for research purposes [57]." (p. 64)
  • Differential Diagnosis: It is important to differentiate AD from other causes of dementia and cognitive impairment, such as vascular dementia, Lewy body dementia, and frontotemporal dementia.
  • Treatment and Management: Current treatments for AD are primarily symptomatic and aim to manage cognitive and behavioral symptoms. "Disease-modifying treatments, i.e. those proven to alter the underlying disease pathology or disease course, are not yet available." (p. 64) Acetylcholinesterase inhibitors (AChEIs) and memantine are the mainstay of symptomatic treatment. Non-pharmacological approaches, including cognitive stimulation and exercise, are also important components of management.
  • Future Prospects: Future research is focused on developing disease-modifying therapies that target the underlying pathology, such as amyloid and tau. This includes "antibody-based approaches to amyloid clearance [67]." (p. 67) There is a strong emphasis on identifying individuals at risk and intervening earlier in the disease process, including in the preclinical stage. "The identification of novel drug targets are already leading to the identification of novel drug targets." (p. 67) Personalized medicine approaches, utilizing genetic and biomarker information, are also seen as a key future direction.
    • Conclusion

    The review article highlights the significant progress made in understanding Alzheimer's disease, particularly regarding its genetic and pathological basis. However, it also underscores the urgent need for effective disease-modifying treatments and improved diagnostic tools, especially for early and accurate identification of individuals at risk. The future of AD research lies in a deeper understanding of the complex interplay of factors contributing to the disease, the development of targeted therapies, and the implementation of strategies for early intervention and personalized medicine.

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    Jack’s Podcast on Slowing AgingBy jack Lejeune