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

Author

Listed:
  • Matthias Arnold

    (Duke University
    Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health)

  • 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
    University of Arizona
    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
    Macquarie University)

  • Michael W. Weiner

    (San Francisco VA Medical Center/University of California San Francisco)

  • Eugenia Trushina

    (Mayo Clinic
    Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic)

  • Jon B. Toledo

    (University of Pennsylvania
    Houston Methodist Hospital)

  • 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
    Duke University
    Duke University)

  • Andrew J. Saykin

    (Indiana University School of Medicine)

  • Rima Kaddurah-Daouk

    (Duke University
    Duke University
    Duke University)

  • Gabi Kastenmüller

    (Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health
    German Center for Diabetes Research (DZD))

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.

Suggested Citation

  • 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 , 2020. "Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14959-w
    DOI: 10.1038/s41467-020-14959-w
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    Cited by:

    1. Tianlu Chen & Fengfeng Pan & Qi Huang & Guoxiang Xie & Xiaowen Chao & Lirong Wu & Jie Wang & Liang Cui & Tao Sun & Mengci Li & Ying Wang & Yihui Guan & Xiaojiao Zheng & Zhenxing Ren & Yuhuai Guo & Lu , 2024. "Metabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Alice S. Tang & Tomiko Oskotsky & Shreyas Havaldar & William G. Mantyh & Mesude Bicak & Caroline Warly Solsberg & Sarah Woldemariam & Billy Zeng & Zicheng Hu & Boris Oskotsky & Dena Dubal & Isabel E. , 2022. "Deep phenotyping of Alzheimer’s disease leveraging electronic medical records identifies sex-specific clinical associations," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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