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.

doi:10.1101/2024.10.17.618322

bioRxiv · 10.1101/2024.10.17.618322

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.

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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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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.. 2024-10-17. APOE Genotype and Biological Age Impact Inter-Omic Associations Related to Bioenergetics. https://doi.org/10.1101/2024.10.17.618322

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