APOE genotype and biological age impact inter-omic associations related to bioenergetics
Publication Title
Aging (Albany NY)
Document Type
Article
Publication Date
5-3-2025
Keywords
Humans; Male; Female; Aging; Aged; Genotype; Apolipoproteins E; Energy Metabolism; Aged, 80 and over; Middle Aged; Insulin Resistance; Longevity; Alleles; Alzheimer’s disease (AD); apolipoprotein E (APOE); biological age; insulin resistance; metabolism.; washington; isb; genomics
Abstract
Apolipoprotein E (APOE) modifies human aging; specifically, the ε2 and ε4 alleles are among the strongest genetic predictors of longevity and Alzheimer's disease (AD) risk, respectively. However, detailed mechanisms for their influence on aging remain unclear. In the present study, we analyzed multi-omic association patterns across APOE genotypes, sex, and biological age (BA) axes in 2,229 community dwelling individuals. Our analysis, supported by validation in an independent cohort, identified diacylglycerols as the top APOE-associated plasma metabolites. However, despite the known opposing aging effects of the allele variants, both ε2- and ε4-carriers showed higher diacylglycerols compared to ε3-homozygotes. 'Omics association patterns of ε2-carriers and increased biological age were also counter-intuitively similar, displaying significantly increased associations between insulin resistance markers and energy-generating pathway metabolites. These results demonstrate the context-dependence of the influence of APOE, with ε2 potentially strengthening insulin resistance-like pathways in the decades prior to imparting its longevity benefits. Additionally, they provide an atlas of APOE-related 'omic associations and support the involvement of bioenergetic pathways in mediating the impact of APOE on aging.
DOI
10.18632/aging.206243
