APOE genotype and biological age impact inter-omic associations related to bioenergetics

Authors: ELLIS, DYLAN - Institute For Systems Biology; WATANABE, KENGO - Institute For Systems Biology; WILMANSKI, TOMASZ - Institute For Systems Biology; LUSTGARTEN, MICHAEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ARDISSON KORAT, ANDRES - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; GLUSMAN, GWENLYN - Institute For Systems Biology; HADLOCK, JENNIFER - Institute For Systems Biology; FIEHN, OLIVER - University Of California, Davis; SEBASTIANI, PAOLA - Tufts Medical Center; PRICE, NATHAN - Thorne Healthtech; HOOD, LEROY - Institute For Systems Biology; MAGIS, ANDREW - Institute For Systems Biology; EVANS, SIMON - Phenome Health; PFLIEGER, LANCE - Phenome Health; LOVEJOY, JENNIFER - Institute For Systems Biology; GIBBONS, SEAN - Institute For Systems Biology; FUNK, CORY - Institute For Systems Biology; BALONI, PRIYANKA - Purdue University; RAPPAPORT, NOA - Institute For Systems Biology

Submitted to: Trade Journal Publication
Publication Type: Trade Journal
Publication Acceptance Date: 4/22/2025
Publication Date: 5/3/2025
Citation: Ellis, D., Watanabe, K., Wilmanski, T., Lustgarten, M., Ardisson Korat, A., Glusman, G., Hadlock, J., Fiehn, O., Sebastiani, P., Price, N., Hood, L., Magis, A.T., Evans, S.J., Pflieger, L., Lovejoy, J.C., Gibbons, S.M., Funk, C.C., Baloni, P., Rappaport, N. 2025. APOE genotype and biological age impact inter-omic associations related to bioenergetics. Trade Journal Publication. https://doi.org/10.18632/aging.206243.
DOI: https://doi.org/10.18632/aging.206243

Interpretive Summary: Some people age more healthily than others, and some are more likely to develop diseases like Alzheimer's. A common gene that comes in different forms plays a role in these differences, but we do not know the mechanisms that explain why it affects people so differently. This study looked at data from 2,229 adults and found that blood molecules linked to how the body uses energy are associated with this gene, regardless of whether it corresponds to the form that increases or reduces disease risk. This surprising finding challenges what we thought we knew about how this gene affects aging. Understanding how this gene interacts with everyday body processes could help us find better ways to support healthy aging and brain health. In the long term, this research could guide new strategies for preventing age-related diseases, improving quality of life, and reducing healthcare costs.

Technical Abstract: Apolipoprotein E (APOE) modifies human aging; specifically, the e2 and e4 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 e2- and e4-carriers showed higher diacylglycerols compared to e3-homozygotes. Omics association patterns of e2-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 e2 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.