The Genetics of Cognitively Healthy Centenarians

The overall objective of this thesis was to investigate the genetic factors underlying extreme human longevity and the escape of Alzheimer’s disease, for which we explore the genetic architecture of the cognitively healthy centenarians from the 100-plus Study. In the first part of the thesis, we focus on the comparison of the cognitively healthy centenarians with young AD patients and population controls in the context of Alzheimer’s disease and human longevity. In chapter 2, we exploited extreme phenotypes in the genetic research of AD by comparing extreme controls and young AD cases in a case-control study of AD. We report that cognitively healthy centenarians have a lower frequency of genetic variants associated with increased AD risk compared to the general population, and a higher frequency of protective genetic variants. In chapter 3, we investigated the molecular pathways that are known to play a role in AD pathogenesis and their association with the resilience against AD. In this study, we combined the effect of multiple variants together into polygenic risk scores (PRS) and pathway- specific polygenic risk scores, which incorporate the effect of multiple genetic variants acting on the same molecular pathway. We report that cognitively healthy centenarians have the lowest PRS and pathway-specific PRS for all major AD-associated pathways. Moreover, only the PRS of immune system and endocytosis pathways significantly influenced the resilience against AD, even after excluding APOE variants. In chapter 4, we attempted to disentangle the effect on longevity from the effect on AD risk of the genetic variants that are associated with AD. We found that most genetic variants that increase the risk of AD were associated with lower odds of longevity. Based on our analysis, most AD-associated variants negatively affect longevity through their increased risk of AD. However, a subset of variants preferentially involved in immune-related processes seemed to affect not only AD but also other age-related diseases, such that the cumulative effect on longevity was larger than the effect on AD alone. In chapter 5, we focused on human longevity and we constructed a polygenic risk score (PRS) that associated with becoming a cognitively healthy centenarians and independently with survival. This PRS included 330 genetic variants, did not include APOE variants, associated with up to 4-years longer survival, and showed functional enrichment for hallmarks of longevity. In the second part of the thesis, we present the contribution of the cognitively healthy centenarians from the 100-plus Study to large, collaborative GWAS of AD and longevity. In chapter 6, we participated to one of the largest GWAS of AD. This collaborative effort led to the discovery of six additional genetic variants associated with AD. Furthermore, we add on the growing literature showing the applicability of polygenic risk score (PRS) of AD in order to stratify patients and to identify those at highest risk for the disease. In chapter 7, we collaborated on the largest GWAS of longevity. We introduced a new, unbiased, method to identify cases and controls based on country- and sex-specific survival percentiles. In addition to APOE variants, we found a novel association near GPR78 gene, and through genetic correlation and gene expression analyses, we showed a marked overlap between the genetics of diseases and the genetics of longevity. In chapter 8, we present snpXplorer, a tool freely available to the scientific community to explore summary statistics of genetic studies, compare levels of association between different traits, and functionally annotate sets of genetic variants.