Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome

Matthias Arnold, Kwangsik Nho, Alexandra Kueider-Paisley, Tyler Massaro, Kevin Huynh, Barbara Brauner, Siamak MahmoudianDehkordi, Gregory Louie, M. Arthur Moseley, J. Will Thompson, Lisa St John-Williams, Jessica D. Tenenbaum, Colette Blach, Rui Chang, Roberta D. Brinton, Rebecca Baillie, Xianlin Han, John Q. Trojanowski, Leslie M. Shaw, Ralph MartinsMichael W. Weiner, Eugenia Trushina, Jon B. Toledo, Peter J. Meikle, David A. Bennett, Jan Krumsiek, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk*, Gabi Kastenmüller

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    72 Citations (Scopus)
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    Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.

    Original languageEnglish
    Article number1148
    Pages (from-to)1-12
    Number of pages12
    JournalNature Communications
    Issue number1
    Publication statusPublished - 2 Mar 2020

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    Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.


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