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The Alzheimer’s Disease Metabolome: Effects of Sex and APOE ε4 genotype

Matthias Arnold, View ORCID ProfileKwangsik Nho, View ORCID ProfileAlexandra Kueider-Paisley, Tyler Massaro, Barbara Brauner, View ORCID ProfileSiamak MahmoudianDehkordi, Gregory Louie, M. Arthur Moseley, J. Will Thompson, Lisa St John Williams, Jessica D. Tenenbaum, Colette Blach, Rui Chang, View ORCID ProfileRoberta D. Brinton, Rebecca Baillie, View ORCID ProfileXianlin Han, John Q. Trojanowski, Leslie M. Shaw, Michael W. Weiner, View ORCID ProfileEugenia Trushina, Jon B. Toledo, View ORCID ProfileJan Krumsiek, P. Murali Doraiswamy, View ORCID ProfileAndrew J. Saykin, View ORCID ProfileRima Kaddurah-Daouk, Gabi Kastenmüller, for the Alzheimer’s Disease Neuroimaging Initiative, the Alzheimer’s Disease Metabolomics Consortium
doi: https://doi.org/10.1101/585455
Matthias Arnold
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USAInstitute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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Kwangsik Nho
Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA
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  • ORCID record for Kwangsik Nho
Alexandra Kueider-Paisley
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
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  • ORCID record for Alexandra Kueider-Paisley
Tyler Massaro
Duke Clinical Research Institute, Duke University, Durham, NC, USA
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Barbara Brauner
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
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Siamak MahmoudianDehkordi
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
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  • ORCID record for Siamak MahmoudianDehkordi
Gregory Louie
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
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M. Arthur Moseley
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
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J. Will Thompson
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
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Lisa St John Williams
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Duke University, Durham, NC, USA
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Jessica D. Tenenbaum
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
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Colette Blach
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
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Rui Chang
Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, USA
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Roberta D. Brinton
Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, USADepartments of Pharmacology and Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA
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  • ORCID record for Roberta D. Brinton
Rebecca Baillie
Rosa & Co LLC, San Carlos, CA, USA
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Xianlin Han
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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John Q. Trojanowski
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Leslie M. Shaw
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Michael W. Weiner
Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA, USA
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Eugenia Trushina
Departments of Neurology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
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  • ORCID record for Eugenia Trushina
Jon B. Toledo
Department of Neurology, Houston Methodist Hospital, Houston, TX, USA
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Jan Krumsiek
Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA
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P. Murali Doraiswamy
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USADuke Institute of Brain Sciences, Duke University, Durham, NC, USADepartment of Medicine, Duke University, Durham, NC, USA
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Andrew J. Saykin
Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA
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  • ORCID record for Andrew J. Saykin
Rima Kaddurah-Daouk
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USADuke Institute of Brain Sciences, Duke University, Durham, NC, USADepartment of Medicine, Duke University, Durham, NC, USA
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  • For correspondence: g.kastenmueller@helmholtz-muenchen.de kaddu001@mc.duke.edu
Gabi Kastenmüller
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, GermanyGerman Center for Diabetes Research (DZD), Neuherberg, Germany
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  • For correspondence: g.kastenmueller@helmholtz-muenchen.de kaddu001@mc.duke.edu
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Abstract

Recent studies have provided evidence that 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. They also both give rise to large metabolic differences, suggesting that metabolic aspects of AD pathogenesis may differ between males and females and between APOE ε4 carriers and non-carriers. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 140 metabolites measured in serum samples of 1,517 AD neuroimaging initiative subjects, with AD biomarkers for Aβ and tau pathology and neurodegeneration. We observed substantial sex differences in effects of 15 metabolites on AD biomarkers with partially overlapping differences for APOE ε4 status groups. These metabolites highlighted several group-specific alterations not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification by both variables uncovered further subgroup-specific metabolic effects limited to the group with presumably the highest AD risk: APOE ε4+ females. Pathways linked to the observed metabolic alterations suggest that females experience more expressed impairment of mitochondrial energy production in AD than males. These findings indicate that dissecting metabolic heterogeneity in AD pathogenesis may enable grading of the biomedical relevance of specific pathways for specific subgroups. Extending our approach beyond simple one- or two-fold stratification may thus guide the way to personalized medicine.

Significance statement Research provides substantial evidence that late-onset Alzheimer’s disease (AD) is a metabolic disease. Besides age, female sex and APOEε4 genotype represent strong risk factors for AD, and at the same time give rise to large metabolic differences. Our systematic investigation of sex and APOE ε4 genotype differences in the link between metabolism and measures of pre-symptomatic AD using stratified analysis revealed several group-specific metabolic alterations that were not observed without sex and genotype stratification of the same cohort. Pathways linked to the observed metabolic alterations suggest females are more affected by impairment of mitochondrial energy production in AD than males, highlighting the importance of tailored treatment approaches towards a precision medicine approach.

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Posted April 25, 2019.
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The Alzheimer’s Disease Metabolome: Effects of Sex and APOE ε4 genotype
Matthias Arnold, Kwangsik Nho, Alexandra Kueider-Paisley, Tyler Massaro, 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, Michael W. Weiner, Eugenia Trushina, Jon B. Toledo, Jan Krumsiek, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, Gabi Kastenmüller, for the Alzheimer’s Disease Neuroimaging Initiative, the Alzheimer’s Disease Metabolomics Consortium
bioRxiv 585455; doi: https://doi.org/10.1101/585455
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The Alzheimer’s Disease Metabolome: Effects of Sex and APOE ε4 genotype
Matthias Arnold, Kwangsik Nho, Alexandra Kueider-Paisley, Tyler Massaro, 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, Michael W. Weiner, Eugenia Trushina, Jon B. Toledo, Jan Krumsiek, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, Gabi Kastenmüller, for the Alzheimer’s Disease Neuroimaging Initiative, the Alzheimer’s Disease Metabolomics Consortium
bioRxiv 585455; doi: https://doi.org/10.1101/585455

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