Neuropathological hallmarks of Alzheimer's disease in centenarians, in the context of aging.

Abstract

Alzheimer's Disease (AD) is characterized by accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs). With increasing age these neuropathological hallmarks are also present in the brains of non-demented individuals. Here, we investigated neuropathological hallmarks in cognitively healthy centenarians in the context of aging. Amyloid phases, Braak stages (NFTs) and CERAD scores (neuritic plaques, NPs) and brain weights of 53 well-phenotyped self-reported cognitively healthy centenarians (aged 100-115) were compared with 1,503 brains from AD- (age 37-102) and non-demented donors (age 16-99). Global cognitive performance (MMSE score) in centenarians was assessed on average 0.83 years before death and correlations with the pathologies were assessed when separating the centenarians on MMSE alone or in combination with AD pathology presence. With increasing age-at-death, average AD neuropathology load increases in non-demented individuals, and decreases in AD cases, converging at around 100 years of age. Of all non-demented centenarians (MMSE score ≥26 at last visit), 50% fulfilled pathology criteria for AD and had intermediate levels of AD neuropathology, and one centenarian (5%) was free of AD pathology. Among centenarians, Amyloid phases, CERAD scores, or brain weight did not correlate with MMSE score. Braak stages varied widely, but did not exceed Braak stage IV. Moreover, Braak stage correlated with cognitive performance (p=0.049). Neuropathology-loads in AD and non-demented individuals converge at 100 years, suggesting that the levels of these pathologies are a common consequence of aging. A large proportion of cognitively healthy centenarians fulfil pathological criteria for AD. These findings suggest that centenarians can have high levels of cognitive health despite the presence of pathology. This may be attributed to the prolonged functioning of cellular processes that maintain brain health in these unique individuals.