Age‐related diseases characteristic of post‐reproductive life, aging, and life span are the examples of polygenic non‐Mendelian traits with intricate genetic architectures. Polygenicity of these traits implies that multiple variants can impact their risks independently or jointly as combinations of specific variants. Here, we examined chances to live to older ages, 85 years and older, for carriers of compound genotypes comprised of combinations of genotypes of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms using data from four human studies. The choice of these polymorphisms was motivated by our prior results showing that the ɛ4 carriers having minor alleles of the other two polymorphisms were at exceptionally high risk of Alzheimer's disease (AD), compared with non‐carriers of the minor alleles. Consistent with our prior findings for AD, we show here that the adverse effect of the ɛ4 allele on survival to older ages is significantly higher in carriers of minor alleles of rs2075650 and/or rs12721046 polymorphisms compared with their non‐carriers. The exclusion of AD cases made this effect stronger. Our results provide compelling evidence that AD does not mediate the associations of the same compound genotypes with chances to survive until older ages, indicating the existence of genetically heterogeneous mechanisms. The survival chances can be mainly associated with lipid‐ and immunity‐related mechanisms, whereas the AD risk, can be driven by the AD‐biomarker‐related mechanism, among others. Targeting heterogeneous polygenic profiles of individuals at high risks of complex traits is promising for the translation of genetic discoveries to health care.

Multifactorial diseases, health-related traits, and lifespan are polygenic phenotypes with complex genetic architectures. Polygenicity implies that multiple variants can impact the risks of these phenotypes independently or jointly. Recently, we showed that carriers of minor alleles of rs429358 (APOE ɛ4 encoding polymorphism), rs2075650 (TOMM40), and rs12721046 (APOC1) polymorphisms have up to 4.4 times higher risk of Alzheimer’s disease (AD) than APOE ɛ4 carriers without the minor alleles of rs2075650 and rs12721046. Here, we examined the chances of living to older ages—85 years and above—for carriers of compound genotypes combining these three polymorphisms using data from the Long Life Family Study, Framingham Heart Study, Cardiovascular Health Study, and UK Biobank. Consistent with their higher AD risk, carriers of the APOE ɛ4 allele with one or two minor alleles of rs2075650 and rs12721046 had 24.3% lower log odds of living to 85+ years (β=-0.243, p=2.22×10-2) than APOE ɛ4 carriers without either minor allele. Counterintuitively, AD did not mediate this risk. With AD-affected subjects excluded from the analysis, the effect size for the log odds of living to 85+ years (β=-0.352, p=2.35×10-3) was 1.45 times larger for APOE ɛ4 carriers with one or two minor alleles of rs2075650 and rs12721046. The chances of survival could be associated with lipid- and immunity-related mechanisms, whereas the risk of AD may be associated with amyloid-β-related mechanisms, among others. Targeting heterogeneous polygenic profiles of individuals at higher risks of multifactorial phenotypes may be a promising strategy for translating genetic discoveries to health care.