The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity

Abstract

Human longevity is influenced by the genetic risk of age-related diseases. As Alzheimer’s disease (AD) represents a common condition at old age, an interplay between genetic factors affecting AD and longevity is expected. We explored this interplay by studying the prevalence of AD-associated single-nucleotide-polymorphisms (SNPs) in cognitively healthy centenarians, and replicated findings in a parental-longevity GWAS. We found that 28/38 SNPs that increased AD-risk also associated with lower odds of longevity. For each SNP, we express the imbalance between AD- and longevity-risk as an effect-size distribution. Based on these distributions, we grouped the SNPs in three groups: 17 SNPs increased AD-risk more than they decreased longevity-risk, and were enriched for β-amyloid metabolism and immune signaling; 11 variants reported a larger longevity-effect compared to their AD-effect, were enriched for endocytosis/immune-signaling, and were previously associated with other age-related diseases. Unexpectedly, 10 variants associated with an increased risk of AD and higher odds of longevity. Altogether, we show that different AD-associated SNPs have different effects on longevity, including SNPs that may confer general neuro-protective functions against AD and other age-related diseases.

Long-Lived Individuals Show a Lower Burden of Variants Predisposing to Age-Related Diseases and a Higher Polygenic Longevity Score

“…The literature supports a link between disease-associated variants and human longevity, within and beyond the TOMM40/APOE/APOC1 gene region [14,19,26,27]. Our results substantiated the relatively well-documented shared genetic component of longevity and predisposition to cardiovascular disease (CVD; significantly lower risk scores for CAD, AF and ISS in LLI compared to controls) as well as the genetic link with AD [14,15,[18][19][20]28]. Additionally, we strengthened the evidence of a shared genetic architecture between longevity and T2D, as already indicated in, e.g., [15,20].…”

“…For example, Fortney et al successfully applied a disease-informed GWAS approach to detect new longevity genes [14]. They reported a large genetic overlap between longevity and AD and CAD, respectively, which is supported by other studies (e.g., [15,[18][19][20]). For other ARDs, such as T2D, the evidence for a possible genetic link with human longevity is less clear (see, e.g., [14,15,20,21]).…”

Are Alzheimer's and coronary artery diseases genetically related to longevity?

“…Interestingly, rs10818576-G, rs10774624-G, and rs1964272-G were associated with higher odds of developing CAD and lower odds of getting AD and surviving past 90 years old, whereas rs9630903-G was found to be protective of CAD but increasing the odds of developing AD and living longer. These directions of effects seem unexpected, however a previous study (10) reported ten similar variants whose unexpected direction of effect was replicated for only two of the SNPs. The authors suggested that these effects could be the result of interactions among variants, known as epistasis.…”

“…This could be due to an increased prevalence of protective alleles for the diseases under study that could lead to the delay of disease onset or to the decrease of the severity. Tesi et al (10) explored the genetic architecture between AD and longevity by studying the effect of 38 AD-associated genetics variants on longevity, and they showed that 74% of the AD risk alleles are associated with lower odds of becoming a centenarian. Finally, in a recent study by Martin and Fraser (11) the authors suggested that part of the pathogenesis of the ARDs might be partly regulated by loci that control gene expression over age.…”

Genetic trade‐offs between complex diseases and longevity

“…However, conflicting correlational evidence was reported between longevity and T2D (Beekman et al, 2010; Deelen et al, 2019; Erikson et al, 2016; McDaid et al, 2017). Recently, one study showed that most risk SNPs of the Alzheimer's disease (AD) associated with decreased odds of longevity, but some SNPs increased the probability of both AD and longevity (Tesi et al, 2021).…”