The Exceptional Vulnerability of Humans to Alzheimer’s Disease

Abstract

Like many humans, nonhuman primates deposit copious misfolded Aβ protein in the brain as they age. Nevertheless, the complete behavioral and pathologic phenotype of Alzheimer’s disease (AD), including Aβ plaques, neurofibrillary (tau) tangles, and dementia, has not yet been identified in a nonhuman species. Recent research suggests that the crucial link between Aβ aggregation and tauopathy is somehow disengaged in aged monkeys. Understanding why AD fails to develop in species that are biologically proximal to humans could disclose new therapeutic targets in the chain of events leading to neurodegeneration and dementia.

Selective neuronal vulnerability in Alzheimer’s disease: a network-based analysis

“…This confirms the validity of leveraging the power of ex vivo neuron-specific molecular profiles in the mouse to gain relevant insight into the molecular characteristics of the most vulnerable neurons in human AD. While there are differences in lifespan and other factors relevant to AD that may facilitate the degeneration of human neurons 35 , our comparison supports the notion that physiological differences between vulnerable and resistant neurons are conserved. Our study provides, to our knowledge, the first systematic evidence that the molecular identity of AD-relevant cell types is conserved between the mouse and human brain.…”

Deposition of phosphorylated amyloid‐β in brains of aged nonhuman primates and canines

“…Primates and canines not only develop Ab pathology resembling that of humans, but also show cognitive decline during the natural ageing process. Ab accumulates in different regions of the brain in a manner that parallels the distribution pattern in the human AD brain (2,3,5,13). Nonhuman primates also represent a valuable model to study AD pathogenesis owing to their close evolutionary relationship to humans.…”

“…Nonhuman primates also represent a valuable model to study AD pathogenesis owing to their close evolutionary relationship to humans. The age-associated neurodegeneration reported in nonhuman primates is associated with brain atrophy, abundant amyloid plaques and a loss of cholinergic neurons similar to human AD (2,13). However, nonhuman primates and canines show little if any neurofibrillary tangle pathology, suggesting that these species develop neuropathological features resembling early phases of AD pathogenesis (13).…”

“…Ab in the wall of a cerebral blood vessel could affect brain circulation, the blood-brain barrier and cause microhaemorrhages (10). Previous reports indicate that the age-related neuropathological lesions and cognitive impairment in aged canine and vervets is comparable to that of humans, suggesting that these species could represent natural animal models of sporadic cerebral amyloidosis to study the mechanisms involved in the development and progression of AD (2,3,5,13). Post-translationally modified Ab variants are abundant in the human brain and likely contribute to the complex pathways of Ab aggregation, deposition and neurotoxicity.…”

Human-lineage-specific genomic elements: relevance to neurodegenerative disease and APOE transcript usage

“…Humans are perceived to be particularly vulnerable to neurodegenerative disorders relative to other primates on both a pathological and phenotypic level [1][2][3][4][5] . This is exemplified in Alzheimer's disease, in which a similar phenotype is not seen in ageing non-human primates, nor are the characteristic neurofibrillary tangles on pathological examination 1,6 . Likewise, Parkinson's disease does not naturally occur in non-human primates, whose motor deficits do not respond to levodopa administration and a Lewy body pathological burden is not present 5,7 .…”