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Nat Commun. 2020 Mar 2;11(1):1148. doi: 10.1038/s41467-020-14959-w.

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

Author information

1
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
2
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
3
Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
4
Duke Clinical Research Institute, Duke University, Durham, NC, USA.
5
Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
6
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA.
7
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
8
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
9
Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, USA.
10
Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
11
Department of Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA.
12
Rosa & Co LLC, San Carlos, CA, USA.
13
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
14
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
15
School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia.
16
Department of Biomedical Sciences, Macquarie University, North Ryde, NSW, Australia.
17
Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA, USA.
18
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
19
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
20
Department of Neurology, Houston Methodist Hospital, Houston, TX, USA.
21
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
22
Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
23
Duke Institute of Brain Sciences, Duke University, Durham, NC, USA.
24
Department of Medicine, Duke University, Durham, NC, USA.
25
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA. kaddu001@mc.duke.edu.
26
Duke Institute of Brain Sciences, Duke University, Durham, NC, USA. kaddu001@mc.duke.edu.
27
Department of Medicine, Duke University, Durham, NC, USA. kaddu001@mc.duke.edu.
28
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. g.kastenmueller@helmholtz-muenchen.de.
29
German Center for Diabetes Research (DZD), Neuherberg, Germany. g.kastenmueller@helmholtz-muenchen.de.

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.

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