Apolipoprotein E () 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 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 -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 , with ε2 potentially strengthening insulin resistance-like pathways in the decades prior to imparting its longevity benefits. Additionally, they provide an atlas of -related 'omic associations and support the involvement of bioenergetic pathways in mediating the impact of on aging.