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.
| Original language | English |
|---|---|
| Article number | 1148 |
| Number of pages | 12 |
| Journal | Nature Communications |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Dec 2020 |
| Externally published | Yes |
Cite this
- APA
- Author
- BIBTEX
- Harvard
- Standard
- RIS
- Vancouver
}
In: Nature Communications, Vol. 11, No. 1, 1148, 01.12.2020.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome
AU - Arnold, Matthias
AU - Nho, Kwangsik
AU - Kueider-Paisley, Alexandra
AU - Massaro, Tyler
AU - Huynh, Kevin
AU - Brauner, Barbara
AU - MahmoudianDehkordi, Siamak
AU - Louie, Gregory
AU - Moseley, M. Arthur
AU - Thompson, J. Will
AU - John-Williams, Lisa St
AU - Tenenbaum, Jessica D.
AU - Blach, Colette
AU - Chang, Rui
AU - Brinton, Roberta D.
AU - Baillie, Rebecca
AU - Han, Xianlin
AU - Trojanowski, John Q.
AU - Shaw, Leslie M.
AU - Martins, Ralph
AU - Weiner, Michael W.
AU - Trushina, Eugenia
AU - Toledo, Jon B.
AU - Meikle, Peter J.
AU - Bennett, David A.
AU - Krumsiek, Jan
AU - Doraiswamy, P. Murali
AU - Saykin, Andrew J.
AU - Kaddurah-Daouk, Rima
AU - Kastenmüller, Gabi
N1 - Funding Information: P.M.D. has received research grants (through Duke University) from Avid/Lilly, Neuronetrix, Avanir, Salix, Alzheimer’s Drug Discovery Foundation, DOD and NIH. P.M.D. has received speaking or advisory fees from Anthrotronix, Neuroptix, Geno-mind, Clearview, Verily, RBC, Brain Canada, and CEOs Against Alzheimer’s. P.M.D. owns shares in Muses Labs, Anthrotronix, Evidation Health, Turtle Shell Technologies, and Advera Health whose products are not discussed here. P.M.D. served on the board of Baycrest and serves on the board of Apollo Hospitals. P.M.D. is a co-inventor (through Duke) on patents relating to dementia biomarkers, metabolomics, and therapies, which are unlicensed. R.K.D. is inventor on key patents in the field of metabolomics, including applications for Alzheimer disease. M.A., J.B.T., G.K., M.A.M., J.W.T., R.B., X.H., L.S.J.W., A.J.S., K.N. are co-inventors on patent WO2018049268 in this field. J.B.T. further reports investigator-initiated research support from Eli Lilly unrelated to the work reported here. J.Q.T. may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is a co-inventor and he received revenue from the sale of Avid to Eli Lilly as a co-inventor on imaging-related patents submitted by the University of Pennsylvania. L.M.S. is a consultant for Eli Lilly, Novartis, and Roche; he provides QC oversight for the Roche Elecsys immunoassay as part of responsibilities for the ADNI3 study. A.J.S. reports investigator-initiated research support from Eli Lilly unrelated to the work reported here. He has received consulting fees and travel expenses from Eli Lilly and Siemens Healthcare and is a consultant to Arkley BioTek. He also receives support from Springer publishing as an editor-in-chief of Brain Imaging and Behavior. M.W.W. reports stock/stock options from Elan, Synarc, travel expenses from Novartis, Tohoku University, Fundacio Ace, Travel eDreams, MCI Group, NSAS, Danone Trading, ANT Congress, NeuroVigil, CHRU-Hopital Roger Salengro, Siemens, AstraZeneca, Geneva University Hospitals, Lilly, University of California, San Diego–ADNI, Paris University, Institut Catala de Neurociencies Aplicades, University of New Mexico School of Medicine, Ipsen, Clinical Trials on Alzheimer’s Disease, Pfizer, AD PD meeting. All other authors declare no competing interests. Funding Information: Data used in preparation of this article were obtained from the ADNI database (adni.loni. usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http:// adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf. Metabolomics data used in preparation of this article were generated by the Alzheimer’s Disease Metabolomics Consortium (ADMC) and obtained from the AMP-AD Knowledge Portal (https://doi.org/10.7303/syn2580853). As such, the investigators within the ADMC other than named authors provided data but did not participate in analysis or writing of this report. A complete listing of ADMC investigators can be found at: https://sites.duke. edu/adnimetab/team/. Data collection and sharing for this project was funded by the ADNI (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The Religious Orders and the Rush Memory and Aging studies were supported by the National Institute on Aging grants P30AG10161, R01AG15819, R01AG17917, U01AG46152, and U01AG61356. National Institute on Aging (NIA) supported this work (R01 AG059093). NIA also supported the Alzheimer Disease Metabolomics Consortium which is a part of NIA’s national initiatives AMP-AD and M2OVE-AD (R01 AG046171, RF1 AG051550, and 3U01 AG024904-09S4). In addition, M.A., R.K.D., and G.K. are supported by NIA grants RF1 AG058942 and R01 AG057452. M.A. and G.K. are also supported by funding from Qatar National Research Fund NPRP8-061-3-011. K.N. is supported by NIH grants NLM R01 LM012535 and NIA R03 AG054936. X.H. is supported by NIA grant RF1 AG061872. P.M.D. is supported by the NIH, Cure Alzheimer’s Fund and the Karen L. Wrenn Trust. Publisher Copyright: © 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85080889707&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14959-w
DO - 10.1038/s41467-020-14959-w
M3 - Article
C2 - 32123170
AN - SCOPUS:85080889707
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1148
ER -