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A metabolomic signature of the APOE2 allele

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With the goal of identifying metabolites that significantly correlate with the protective e2 allele of the apolipoprotein E (APOE) gene, we established a consortium of five studies of healthy aging and extreme human longevity with 3545 participants. This consortium includes the New England Centenarian Study, the Baltimore Longitudinal Study of Aging, the Arivale study, the Longevity Genes Project/LonGenity studies, and the Long Life Family Study. We analyzed the association between APOE genotype groups E2 (e2e2 and e2e3 genotypes, N = 544), E3 (e3e3 genotypes, N = 2299), and E4 (e3e4 and e4e4 genotypes, N = 702) with metabolite profiles in the five studies and used fixed effect meta-analysis to aggregate the results. Our meta-analysis identified a signature of 19 metabolites that are significantly associated with the E2 genotype group at FDR < 10%. The group includes 10 glycerolipids and 4 glycerophospholipids that were all higher in E2 carriers compared to E3, with fold change ranging from 1.08 to 1.25. The organic acid 6-hydroxyindole sulfate, previously linked to changes in gut microbiome that were reflective of healthy aging and longevity, was also higher in E2 carriers compared to E3 carriers. Three sterol lipids and one sphingolipid species were significantly lower in carriers of the E2 genotype group. For some of these metabolites, the effect of the E2 genotype opposed the age effect. No metabolites reached a statistically significant association with the E4 group. This work confirms and expands previous results connecting the APOE gene to lipid regulation and suggests new links between the e2 allele, lipid metabolism, aging, and the gut-brain axis.

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BLSA was supported by the Intramural Research Program of the National Institute on Aging. We acknowledge Mr. Brendan A. Mitchell for statistical assistance.


NIA R01AG061844 (PS, TTP), NIA U19-AG023122 (to NR, TTP, PS); USDA 58–1950-4–003 (MSL), NHLBI T32-HL083825 (MMM). NIA R01AG057909 (NB, SM), NIA R01AG061155 (SM, NB). NIA U19AG063893 (GJP, TTP), NIA UH2AG064704 (TTP, PS, SM, NB). This project was supported in part by the USDA Agricultural Research Service Cooperative Agreement 58-8050-9-004. The content is the sole responsibility of the authors and does not necessarily represent the official views of the USDA.

The authors declare no competing interests. All study participants provided informed consent and the studies were approved by the Institutions’ IRB as described in the “Methods.”

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Correspondence to Paola Sebastiani.

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Sebastiani, P., Song, Z., Ellis, D. et al. A metabolomic signature of the APOE2 allele. GeroScience 45, 415–426 (2023).

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