Cognitively Healthy Centenarians are genetically protected against Alzheimer's disease specifically in immune and endo-lysosomal systems

Alzheimer's Disease (AD) prevalence increases with age, yet a small fraction of the population reaches ages beyond 100 years without cognitive decline. We aimed to uncover the genetic factors associated with such resilience against AD. Genome-Wide-Association-Studies (GWAS) identified 86 single-nucleotide-polymorphisms (SNPs) associated with AD-risk. We studied each SNP in 2,281 AD-cases, 3,165 middle-aged population controls, and 346 cognitively healthy centenarians, and we combined SNPs into Polygenic Risk Scores (PRS) for each individual. Finally, we investigated the functional properties of the SNPs enriched/depleted in centenarians using snpXplorer. Centenarians were depleted with risk-increasing AD-SNPs and enriched with protective AD-SNPs. The PRS was more than 5-fold lower in centenarians compared to AD cases (p=7.69x10-71) and almost 2-fold lower compared to middle-aged population controls (p=5.83x10-17). The strongest protection was found in ANKH, GRN, TMEM106B, SORT1, EPDR1, PLCG2, RIN3, CD2AP, and APOE associated alleles. As expected, the genetic protection was diluted in the offspring of the centenarians. Becoming a cognitively healthy centenarian is associated with a complex genetic protection against AD, which concentrates on an advantageous functioning of the endo-lysosomal and immune systems, and their effect on amyloid-clearance. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by ABOARD, a public-private partnership receiving funding from ZonMW Nationaal Dementiaprogramma and Health~Holland, Topsector Life Sciences & Health. More than 30 partners, including de Hersenstichting (Dutch Brain Foundation) participate in ABOARD. ### 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: Ethics committee of the Amsterdam University Medical Center gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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. 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 request to the authors.