Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome
Open accessPublished version of a preprint
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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Females experience greater impairment of mitochondrial energy production than males in AD.
“The metabolic alterations described in this work suggest that females experience greater impairment of mitochondrial energy production than males [149].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [149]
Arnold et al. (2020) highlighted sex-specific dysregulations of energy metabolism, energy homeostasis, and stress response in AD.
“Arnold et al. (2020) highlighted the sex-specific dysregulations of energy metabolism, energy homeostasis, and (metabolic/nutrient) stress response, presenting the first evidence and molecular readouts for sex-related metabolic differences in AD [149].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [149]
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References 81 · Cited by 202
Research works printed but not linked: 1
- [54]Jack, C. R., Jr. et al. in Alzheimer’s Association International Conference. 1–57 (Alzheimer’s Association).
- Authors
- Arnold, M., Nho, K., Kueider-Paisley, A., Massaro, T., Huynh, K., Brauner, B., MahmoudianDehkordi, S., Louie, G., Moseley, M. A., Thompson, J. W., John-Williams, L. S., Tenenbaum, J. D., Blach, C., Chang, R., Brinton, R. D., Baillie, R., Han, X., Trojanowski, J. Q., Shaw, L. M., Martins, R., Weiner, M. W., Trushina, E., Toledo, J. B., Meikle, P. J., Bennett, D. A., Krumsiek, J., Doraiswamy, P. M., Saykin, A. J., Kaddurah-Daouk, R., & Kastenmüller, G.
- Affiliations
- Duke University (US)
- Indiana University Indianapolis (US)
- Baker Heart and Diabetes Institute (AU)
- Helmholtz Munich (DE)
- University of Arizona (US)
- Rosa (United States) (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Pennsylvania (US)
- Edith Cowan University (AU)
- San Francisco VA Medical Center (US)
- Mayo Clinic (US)
- Houston Methodist (US)
- Rush University Medical Center (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Kaddurah-Daouk, Rima
- Kastenmüller, Gabi
- ORCID
- Arnold, Matthias
- Nho, Kwangsik
- Massaro, Tyler
- Huynh, Kevin
- MahmoudianDehkordi, Siamak
- Louie, Gregory
- Moseley, M. Arthur
- Tenenbaum, Jessica D.
- Blach, Colette
- Chang, Rui
- Brinton, Roberta D.
- Baillie, Rebecca
- Han, Xianlin
- Trojanowski, John Q.
- Shaw, Leslie M.
- Martins, Ralph
- Weiner, Michael W.
- Trushina, Eugenia
- Toledo, Jon B.
- Meikle, Peter J.
- Bennett, David A.
- Krumsiek, Jan
- Doraiswamy, P. Murali
- Saykin, Andrew J.
- Kaddurah-Daouk, Rima
- Kastenmüller, Gabi
- Venue
- Nature Communications
- Published
- 2020-03-02
- Volume
- 11
- Issue
- 1
- Pages
- 1148-1148
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7052223
- OpenAlex
- W3009710006
- Cited by
- 202
- References
- 81
- Citations by year
- 2026: 29 · 2025: 32 · 2024: 38 · 2023: 38 · 2022: 25 · 2021: 33 · 2020: 7
- FWCI
- 19.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UA Campus Repository (The University of Arizona) (acceptedVersion, cc-by)
- Australasian Journal of Paramedicine (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (RF1 AG058942, R01 AG057452, R03 AG054936, R01 LM012535, RF1 AG061872, P30AG10161, R01AG15819, U01AG46152, U01AG61356, R01 AG046171, RF1 AG051550, 3U01 AG024904-09S4)
- Qatar National Research Fund (NPRP8-061-3-011)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- Alzheimer's disease, serum metabolome, APOE ε4, sex differences, late-onset Alzheimer's disease, mitochondrial energy production, metabolic heterogeneity, Alzheimer's disease biomarkers, personalized medicine
- MeSH terms
- Aged, Alzheimer Disease, Apolipoproteins E, Blood, Female, Genotype, Humans, Male, Mitochondria, Sex Factors, Cohort Studies, Biomarkers, Positron-Emission Tomography, Metabolome
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