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.

Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.

Details

Title
Sex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome
Author
Arnold, Matthias 1   VIAFID ORCID Logo  ; Nho Kwangsik 2 ; Kueider-Paisley Alexandra 3 ; Massaro, Tyler 4 ; Huynh, Kevin 5 ; Brauner, Barbara 6 ; MahmoudianDehkordi Siamak 3 ; Louie, Gregory 3   VIAFID ORCID Logo  ; Arthur, Moseley M 7 ; Will, Thompson J 7 ; John-Williams, Lisa St 7 ; Tenenbaum, Jessica D 8   VIAFID ORCID Logo  ; Blach Colette 9 ; Chang, Rui 10 ; Brinton, Roberta D 11 ; Baillie, Rebecca 12   VIAFID ORCID Logo  ; Han Xianlin 13   VIAFID ORCID Logo  ; Trojanowski, John Q 14   VIAFID ORCID Logo  ; Shaw, Leslie M 14 ; Martins, Ralph 15 ; Weiner, Michael W 16 ; Trushina Eugenia 17 ; Toledo, Jon B 18 ; Meikle, Peter J 5   VIAFID ORCID Logo  ; Bennett, David A 19 ; Krumsiek Jan 20 ; Murali, Doraiswamy P 21 ; Saykin, Andrew J 2   VIAFID ORCID Logo  ; Kaddurah-Daouk Rima 21   VIAFID ORCID Logo  ; Kastenmüller Gabi 22   VIAFID ORCID Logo 

1  Duke University, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
2  Indiana University School of Medicine, Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease Center, Indianapolis, USA (GRID:grid.257413.6) (ISNI:0000 0001 2287 3919) 
3  Duke University, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
4  Duke University, Duke Clinical Research Institute, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
5  Metabolomics Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia (GRID:grid.1051.5) (ISNI:0000 0000 9760 5620) 
6  Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
7  Duke University, Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
8  Duke University, Department of Biostatistics and Bioinformatics, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
9  Duke University, Duke Molecular Physiology Institute, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
10  University of Arizona, Center for Innovation in Brain Science, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X) 
11  University of Arizona, Center for Innovation in Brain Science, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X); University of Arizona, Department of Pharmacology, College of Medicine, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X); University of Arizona, Department of Neurology, College of Medicine, Tucson, USA (GRID:grid.134563.6) (ISNI:0000 0001 2168 186X) 
12  Rosa & Co LLC, San Carlos, USA (GRID:grid.134563.6) 
13  University of Texas Health Science Center at San Antonio, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
14  University of Pennsylvania, Department of Pathology & Laboratory Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972) 
15  Edith Cowan University, School of Medical and Health Sciences, Joondalup, Australia (GRID:grid.1038.a) (ISNI:0000 0004 0389 4302); Macquarie University, Department of Biomedical Sciences, North Ryde, Australia (GRID:grid.1004.5) (ISNI:0000 0001 2158 5405) 
16  San Francisco VA Medical Center/University of California San Francisco, Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
17  Mayo Clinic, Department of Neurology, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X); Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
18  University of Pennsylvania, Department of Pathology & Laboratory Medicine, Philadelphia, USA (GRID:grid.25879.31) (ISNI:0000 0004 1936 8972); Houston Methodist Hospital, Department of Neurology, Houston, USA (GRID:grid.63368.38) (ISNI:0000 0004 0445 0041) 
19  Rush University Medical Center, Rush Alzheimer’s Disease Center, Chicago, USA (GRID:grid.240684.c) (ISNI:0000 0001 0705 3621) 
20  Institute for Computational Biomedicine, Englander Institute for Precision Medicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, USA (GRID:grid.5386.8) (ISNI:000000041936877X) 
21  Duke University, Department of Psychiatry and Behavioral Sciences, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Duke University, Duke Institute of Brain Sciences, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961); Duke University, Department of Medicine, Durham, USA (GRID:grid.26009.3d) (ISNI:0000 0004 1936 7961) 
22  Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525); German Center for Diabetes Research (DZD), Neuherberg, Germany (GRID:grid.452622.5) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-14959-w
ProQuest document ID
2369854524
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.