Some evolutionary perspectives on Alzheimer's disease pathogenesis and pathology

Abstract

There is increasing urgency to develop effective prevention and treatment for Alzheimer's disease (AD) as the aging population swells. Yet, our understanding remains limited for the elemental pathophysiological mechanisms of AD dementia that may be causal, compensatory, or epiphenomenal. To this end, we consider AD and why it exists from the perspectives of natural selection, adaptation, genetic drift, and other evolutionary forces. We discuss the connection between the apolipoprotein E (APOE) allele and AD, with special consideration to APOE ε4 as the ancestral allele. The phylogeny of AD-like changes across species is also examined, and pathology and treatment implications of AD are discussed from the perspective of evolutionary medicine. In particular, amyloid-β (Aβ) neuritic plaques and paired helical filament tau (PHFtau) neurofibrillary tangles have been traditionally viewed as injurious pathologies to be targeted, but may be preservative or restorative processes that mitigate harmful neurodegenerative processes or may be epiphenoma of the essential processes that cause neurodegeneration. Thus, we raise fundamental questions about current strategies for AD prevention and therapeutics.

What is normal in normal aging? Effects of aging, amyloid and Alzheimer's disease on the cerebral cortex and the hippocampus

“…Although the atrophy-driving mechanisms may be related to Aβ, the causal role of amyloid in neurodegeneration in healthy older adults remains an open question. Such an account may call for a revision of the prevailing view of amyloid biomarkers in normal aging and AD, in that healthy aging and AD may have partly common neural mechanisms for brain atrophy (see also (Glass and Arnold, 2012)). A critical issue may thus be the regional distribution of Aβ, not only the amount (see Figure 16).…”

Parkinson Disease: An Evolutionary Perspective

“…However, Alzheimer disease and PD are considered specific to Homo sapiens (13–15). While there are useful animal models of PD including MPTP and alpha-synuclein-overexpressing transgenic mouse models, which may recapitulate important clinical features of the human disorders (5, 14), especially in aged monkeys (16, 17), no spontaneous akinetic-rigid syndrome is known to occur in wild mammals including non-human primates.…”

Amyotrophic lateral sclerosis: Origins traced to impaired balance between neural excitation and inhibition in the neonatal period

“…Neurodegenerative disorders are not traditionally considered developmental diseases, but a potential role for complications during pregnancy and childhood has been hypothesized in the etiology of Parkinson disease (PD), although no specific factor has so far been identified . Furthermore, Alzheimer disease (AD) has been suggested to originate during early life, and the presence of apolipoprotein E and small head circumference in children have been linked to an increased risk of AD . Normal functioning of the central nervous system (CNS) in the adult requires correctly timed events during development, and, if neuronal networks are improperly developed, there can be life‐long effects .…”