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Mediation of the APOE associations with Alzheimer’s and coronary heart diseases through body mass index and lipids

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Abstract

The APOE ε2/ε3/ε4 polymorphism is associated with multiple non-Mendelian traits, including high- (HDL-C) and low- (LDL-C) density lipoprotein cholesterol, triglycerides, body mass index (BMI), coronary heart disease (CHD), and Alzheimer’s disease (AD). Lipids and BMI are risk factors for AD and CHD. Causal connections between the ε2 and ε4 alleles and these traits remain, however, poorly understood. We leverage comprehensive analyses of longitudinal data from four studies to examine potentially causal heterogeneous connections between these alleles, lipids, BMI, and diseases. We emphasize mutual mediation roles of lipids and BMI in their associations with the ε2 and ε4 alleles and their mediation roles in the associations of these alleles with AD and CHD. We confirmed previously reported significant univariate associations of these alleles with each trait, except CHD. We found, however, that most of the univariate- and mediation-analysis associations were affected by antagonistic heterogeneity/mediation. The mutual mediation analysis identified the associations of the APOE alleles with LDL-C as the least heterogeneous. The ε2 and ε4 alleles were associated with CHD through lipids, led by beneficial (βIE =  − 0.071, pIE = 2.28 × 10−10) and adverse (βIE = 0.019, pIE = 7.37 × 10−6) associations, respectively, through LDL-C. Both these alleles were adversely associated with CHD through triglycerides. For AD, only BMI partially mediated the adverse association of the ε4 allele with AD (βIE = 0.016, pIE = 2.09 × 10−2). Our results suggest different roles of BMI and lipids in the AD and CHD pathogeneses. More comprehensive studies of causal connections between genetic variants and non-Mendelian traits are required as they can be critically affected by heterogeneous antagonistic relationships.

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Data availability

This manuscript was prepared using limited access data obtained though dbGaP from ARIC study (phs000280.v5.p1), CHS (phs000287.v5.p1), FHS (phs000007.v28.p10), MESA (phs000209.v13.p3), and LOADFS (phs000168.v2.p2).

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Funding

This research was supported by Grants P01 AG043352, R01 AG047310, R01 AG061853, R01 AG065477, and R01AG070488 from the National Institute on Aging. The funding source did not participate in the writing of the manuscript or the decision to submit the manuscript for publication. See also Supplementary Acknowledgment Text.

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  1. Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC, 27708-0408, USA

    Yury Loika, Fan Feng, Elena Loiko & Alexander M. Kulminski

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  1. Yury Loika
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  2. Fan Feng
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  3. Elena Loiko
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  4. Alexander M. Kulminski
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A.M.K. conceived and designed the experiment and wrote the paper; Y.L. designed the experiment, performed statistical analyses, and wrote the paper; F.F. performed statistical analyses; E.L. wrote the paper.

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Correspondence to Yury Loika or Alexander M. Kulminski.

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Loika, Y., Feng, F., Loiko, E. et al. Mediation of the APOE associations with Alzheimer’s and coronary heart diseases through body mass index and lipids. GeroScience 44, 1141–1156 (2022). https://doi.org/10.1007/s11357-021-00458-3

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