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

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
Pages (from-to)748781
JournalFrontiers in Genetics
Publication statusPublished - 2021

Bibliographical note

Copyright © 2021 Tesi, Hulsman, van der Lee, Jansen, Stringa, van Schoor, Scheltens, van der Flier, Huisman, Reinders and Holstege.


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