Diseases of the Nervous System - Chapter 4: Aging, Dementia, and Alzheimer Disease

Diseases of the Nervous System (Second Edition), 2021, Pages 81-107
Harald Sontheimer

In most individuals, aging is a normal, healthy process and typically does not overtly impair cognition and memory function. However, aging is often feared, since it is the greatest risk factor for developing dementia and Alzheimer disease (AD). Affecting over 43 million people worldwide, AD is the single most common neurodegenerative disease. This number is expected to increase further, as average life expectancy is increasing, particularly in the developing world. The pathological hallmarks of AD are neurofibrillary tangles composed of phosphorylated tau protein and amyloid plaques resulting from aggregated β-amyloid. These are usually identified on autopsy, although recent novel imaging techniques now allow detection of amyloid plaques long before patients become symptomatic. Recent studies suggest that an accumulation of misfolded proteins precedes the onset of cognitive symptoms and dementia by at least a decade. Whether and how plaques and tangles are causal of disease or the consequence thereof remains unknown. Genetic studies show up to a 15-fold increased incidence for sporadic AD in people who carry the ε4 allele of apolipoprotein E. Rare, early-onset familiar forms of AD are often associated with mutations in the amyloid precursor protein (APP) or the genes for the APP cleaving enzymes presenilin-1 and 2. These findings suggest that protein deposits are likely to be disease causing. AD is currently incurable and the majority of research efforts are focused on identifying preventive strategies to delay the onset of disease, ideally pushing it past the normal human life span.