Resistance to cortical amyloid-beta associates with cognitive health in centenarians

BACKGROUND Amyloid-beta(Aβ)-plaques accumulate in non-demented individuals, particularly at advanced ages. The unclear association between Aβ-pathology and cognition in elderly raises the question whether Aβ-pathology should be considered a benign consequence of aging. METHODS Post-mortem brains of 95 centenarians and 27 Alzheimer’s disease(AD) patients were evaluated for Aβ-plaque distribution according to the Thal phase and quantitative Aβ-load in the neocortex. For centenarians, Aβ-pathology was correlated to APOE -genotype and performance on 12 cognitive tests administered shortly before death. FINDINGS While 35% of centenarians exhibited Aβ-loads similar to AD patients, cortical Aβ-load was limited in 65% of centenarians, some of which had the highest Thal phase. Cortical Aβ-load, as opposed to Thal phase, associated with APOE -genotype and cognitive performance in centenarians. DISCUSSION Despite increasing Aβ-accumulation in various brain regions with age, actual Aβ-loads remain low in cognitively healthy centenarians. Therefore, Aβ-pathology in the oldest-old may not be considered a benign consequence of aging. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by BrightFocus A2021031S, VUmc foundation, and Surf Sara (Surf 2022.031). H.H is supported by ABOARD, a public-private partnership receiving funding from ZonMw (73305095007) and Health∼Holland, Topsector Life Sciences & Health (PPP-allowance; LSHM20106), the Hans und Ilse Breuer Stiftung (2020), the HorstingStuit Foundation (2018), and the Dutch Research Council (Aspasia premie 015.016.059). The funders of the study had no role in the design of the study, data collection, data analysis, data interpretation, or writing of the report. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The 100-plus Study was approved by the local medical ethics committee of the VUmc (registration 2016.440) and all participants gave informed consent. Brain autopsies were performed by the Netherlands Brain Bank (NBB; Amsterdam, The Netherlands (), as approved by the local medical ethics committee of the VUmc (registration 2009.148). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][1]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: http://ClinicalTrials.gov