The brains of cognitively healthy centenarians: What does the healthy aged brain tell us about Alzheimer’s disease?

Life expectancy has increased tremendously over the last decades, but these extra years are not always spent in good health. The incidence of age-related diseases, such as Alzheimer’s disease (AD), increases sharply after the age of 65, and no cure is available. The associated neuropathological hallmarks have been found to be near universal at ages above 80, but we do not yet fully understand which changes are due to aging, and which ones are exclusively related to the disease, as many older AD patients display a multitude of neuropathological hallmarks in their brains. Reports of individuals like Mrs. Andel-Schipper, who died at age 115 with intact cognitive function, are fascinating examples that show that maintaining cognitive function until these extreme ages is possible. The 100-plus Study investigates centenarians that self-report to be cognitively healthy. They represent an ideal study population to investigate healthy aging and the diseases that are usually associated with it.
This thesis focuses on the brains of these special individuals and aims to get insight into the biological processes associated with cognitive health at old age. It focused on the association between neuropathological substrates of centenarian brains and neuropsychological performance, and the identification of proteins potentially associated with maintenance of cognitive performance at extreme ages. We observed that tau pathology was universally present, while amyloid β was present in the majority of cases. This is in line with the observed increase of AD-associated neuropathologies in non-demented individuals with increasing age, while they decrease in AD cases with age. Only a few centenarians had low pathology levels, indicating resistance to these pathologies as was found for Mrs. Andel-Schipper. In contrast, some individuals with the highest cognitive performance had high levels, indicating resilience. Pathologies such as GVD, ARTAG and atherosclerosis were universal in the brains of centenarians, while TDP-43, CAA, Lewy bodies and infarcts were less prevalent. Taken together, this suggests that the sole presence of such pathologies is not sufficient to cause cognitive decline, and other factors contribute.
This thesis also explored the proteome of the temporal lobe to identify changes with age or tau pathology. We found that for key age-related proteins, the centenarians display abundances of proteins similar to controls of a median 18-years and up to almost 30 years younger than their chronological age. We also compared the abundance of Braak stage-related proteins in AD cases and centenarians at the same Braak stage (IV) and identified proteins that may contribute to the resilience mechanisms against the presence of this pathology in the centenarians.
In conclusion, this thesis provides a comprehensive overview of the characteristics observed in the brains of centenarians that self-report to be cognitively healthy and highlights how the process of aging and AD are entangled. It underlines the importance of studying centenarians to understand healthy brain aging, and in extension, diseases like AD.