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 Martins, Michael W. Weiner, Eugenia Trushina, Jon B. Toledo, Peter J. Meikle, David A. Bennett, Jan Krumsiek, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk () and Gabi Kastenmüller ()
Additional contact information
Matthias Arnold: Duke University
Kwangsik Nho: Indiana University School of Medicine
Alexandra Kueider-Paisley: Duke University
Tyler Massaro: Duke University
Kevin Huynh: Metabolomics Laboratory, Baker Heart and Diabetes Institute
Barbara Brauner: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health
Siamak MahmoudianDehkordi: Duke University
Gregory Louie: Duke University
M. Arthur Moseley: Duke University
J. Will Thompson: Duke University
Lisa St John-Williams: Duke University
Jessica D. Tenenbaum: Duke University
Colette Blach: Duke University
Rui Chang: University of Arizona
Roberta D. Brinton: University of Arizona
Rebecca Baillie: Rosa & Co LLC
Xianlin Han: University of Texas Health Science Center at San Antonio
John Q. Trojanowski: University of Pennsylvania
Leslie M. Shaw: University of Pennsylvania
Ralph Martins: Edith Cowan University
Michael W. Weiner: San Francisco VA Medical Center/University of California San Francisco
Eugenia Trushina: Mayo Clinic
Jon B. Toledo: University of Pennsylvania
Peter J. Meikle: Metabolomics Laboratory, Baker Heart and Diabetes Institute
David A. Bennett: Rush University Medical Center
Jan Krumsiek: Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine
P. Murali Doraiswamy: Duke University
Andrew J. Saykin: Indiana University School of Medicine
Rima Kaddurah-Daouk: Duke University
Gabi Kastenmüller: Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14959-w

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