APOE Genotype and Biological Age Impact Inter-Omic Associations Related to Bioenergetics
Ellis, D. S.; Watanabe, K.; Wilmanski, T.; Lustgarten, M. S.; Ardisson Korat, A. V.; Hadlock, J. J.; Fiehn, O.; Sebastiani, P.; Price, N. D.; Hood, L.; Magis, A. T.; Evans, S. J.; Pflieger, L.; Lovejoy, J. C.; Gibbons, S. M.; Funk, C. C.; Baloni, P.; Rappaport, N.
Show abstract
Apolipoprotein E (APOE) modifies human aging; specifically, the {varepsilon}2 and {varepsilon}4 alleles are among the strongest genetic predictors of longevity and Alzheimers disease (AD) risk, respectively. However, detailed mechanisms for their influence on aging remain unclear. Herein, we analyzed inter-omic, context-dependent association patterns across APOE genotypes, sex, and health axes in 2,229 community-dwelling individuals to test APOE genotypes for variation in metabolites and metabolite-associations tied to a previously-validated metric of biological aging (BA) based on blood biomarkers. Our analysis, supported by validation in an independent cohort, identified top APOE-associated plasma metabolites as diacylglycerols, which were increased in {varepsilon}2-carriers and trended higher in {varepsilon}4-carriers compared to {varepsilon}3-homozygotes, despite the known opposing aging effects of the allele variants. Omics association patterns of {varepsilon}2-carriers and increased biological age were also counter-intuitively similar, displaying increased associations between insulin resistance markers and energy-generating pathway metabolites. These results provide an atlas of APOE-related omic associations and support the involvement of bioenergetic pathways in mediating the impact of APOE on aging.
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