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

BACKGROUNDAlzheimers 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. METHODSGenome-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. RESULTSCentenarians 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. DISCUSSIONBecoming 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.