Alzheimer's Disease Associated Genetic Variants Have Varying Correlations with Longevity

As a general rule, one should take with a grain of salt the results of any individual study on gene variants and correlations with longevity or disease risk. The results rarely replicate. Longevity in particular is a complex emergent phenomenon, and any one gene variant has only a small effect, highly dependent on interactions with environment and other genes. If anything, more rigorous studies of large genetic databases have been steadily decreasing the estimated contribution of genetic variants to variations in human life span. It is near all a matter of culture and lifestyle choice. That said, there are a few well defined gene variants that correlate with Alzheimer's disease risk, those examined in this paper. One should just be a little dubious as to whether the modest correlations with longevity will replicate in other study populations.

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 genome-wide association study (GWAS).

We found that 28 of 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. Most AD-associated variants that increase the risk of the disease are associated with lower odds of longevity. We identified a subset of variants with a larger effect on longevity than on AD, that were previously associated as risk-factors for other age-related diseases, and that are selectively enriched for endocytosis and immune signaling functions, and expressed in microglia and endothelial cells.


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