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

Niccolò Tesi, Marc Hulsman, Sven J. van der Lee, Iris E. Jansen, Najada Stringa, Natasja M. van Schoor, Philip Scheltens, Wiesje M. van der Flier, Martijn Huisman, Marcel J. T. Reinders, Henne Holstege*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Article number748781
JournalFrontiers in Genetics
Publication statusPublished - 21 Dec 2021

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