Abstract
With aging, the incidence of neuropathological hallmarks of neurodegenerative diseases increases in the brains of cognitively healthy individuals. It is currently unclear to what extent these hallmarks associate with symptoms of disease at extreme ages. Forty centenarians from the 100-plus Study cohort donated their brain. Centenarians self-reported to be cognitively healthy at baseline, which was confirmed by a proxy. Objective ante-mortem measurements of cognitive performance were associated with the prevalence, distribution and quantity of age- and AD-related neuropathological hallmarks. Despite self-reported cognitive health, objective neuropsychological testing suggested varying levels of ante-mortem cognitive functioning. Post-mortem, we found that neuropathological hallmarks related to age and neurodegenerative diseases, such as Aβ and Tau pathology, as well as atherosclerosis, were abundantly present in most or all centenarians, whereas Lewy body and pTDP-43 pathology were scarce. We observed that increased pathology loads correlated across pathology subtypes, and an overall trend of higher pathology loads to associate with a lower cognitive test performance. This trend was carried especially by the presence of neurofibrillary tangles (NFTs) and granulovacuolar degeneration (GVD) and to a lesser extent by Aβ-associated pathologies. Cerebral Amyloid Angiopathy (CAA) specifically associated with lower executive functioning in the centenarians. In conclusion, we find that while the centenarians in this cohort escaped or delayed cognitive impairment until extreme ages, their brains reveal varying levels of disease-associated neuropathological hallmarks, some of which associate with cognitive performance.
Highlights
The increase in average life expectancy warrants insight into healthy aging
Whereas Lewy body and phosphorylated TAR DNA-binding protein 43 proteinopathies are usually associated with other neurodegenerative diseases, they often are observed in late-onset Alzheimer’s disease (AD) cases [42]
Full neuropathological characterization was present for 26 brains, partial characterization with staging for phosphorylated TAR DNA-binding protein 43 (pTDP-43) stage and Thal stage granulovacuolar degeneration (GVD)* was present for 35 cases
Summary
The increase in average life expectancy warrants insight into healthy aging. In particular, the study of centenarians might reveal new leads towards healthy aging and potential clues to overcome age-related diseases. The concurrent accumulation of individual pathologies, like CAA, GVD, LB, and pTDP-43, may have an additive effect on the rate of cognitive decline, and contribute to the apparent decrease of the association between NFTs, Aβ and dementia symptoms in older ages [42]. Brains of older dementia patients commonly show less NFT and Aβ pathology compared to younger AD patients [9, 17, 18, 38]. This suggests that, while disease-associated proteinopathies distinguish well between brains from young AD cases and age-matched non-demented controls, this appears more complicated for brains from older individuals. Post-mortem brain assessments of cognitively healthy individuals who reached > 110 years revealed various results: some cognitively healthy centenarians did not accumulate significant pathology, while others appeared to have relatively high levels of pathology [13, 32, 43]
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