Abstract
Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.
| Original language | English |
|---|---|
| Pages (from-to) | 1785-1799 |
| Number of pages | 15 |
| Journal | Alzheimer's and Dementia |
| Volume | 19 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2023 |
Keywords
- APOE
- APP
- PSEN1
- PSEN2
- TREM2
- autosomal dominant Alzheimer's disease
- lipidomics
- metabolomics
- β-citrylglutamate
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In: Alzheimer's and Dementia, Vol. 19, No. 5, 05.2023, p. 1785-1799.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Metabolomic and lipidomic signatures in autosomal dominant and late-onset Alzheimer's disease brains
AU - for the Dominantly Inherited Alzheimer Network (DIAN) Study Group
AU - the Alzheimer's Disease Neuroimaging Initiative
AU - and the Alzheimer's Disease Metabolomics Consortium (ADMC)
AU - Novotny, Brenna C.
AU - Fernandez, Maria Victoria
AU - Wang, Ciyang
AU - Budde, John P.
AU - Bergmann, Kristy
AU - Eteleeb, Abdallah M.
AU - Bradley, Joseph
AU - Webster, Carol
AU - Ebl, Curtis
AU - Norton, Joanne
AU - Gentsch, Jen
AU - Dube, Umber
AU - Wang, Fengxian
AU - Morris, John
AU - Bateman, Randall J.
AU - Perrin, Richard J.
AU - McDade, Eric
AU - Xiong, Chengjie
AU - Chhatwal, Jasmeer
AU - Goate, Alison
AU - Farlow, Martin
AU - Schofield, Peter
AU - Chui, Helena
AU - Karch, Celeste M.
AU - Cruchaga, Carlos
AU - Benitez Viloria, Bruno A.
AU - Harari, Oscar
N1 - Funding Information: Study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by NIA grants P30AG10161 (ROS), R01AG15819 (ROSMAP; genomics and RNAseq), R01AG17917 (MAP), R01AG30146, R01AG36042 (5hC methylation, ATACseq), RC2AG036547 (H3K9Ac), R01AG36836 (RNAseq), R01AG48015 (monocyte RNAseq) RF1AG57473 (single nucleus RNAseq), U01AG32984 (genomic and whole exome sequencing), U01AG46152 (ROSMAP AMP‐AD, targeted proteomics), U01AG46161 (TMT proteomics), U01AG61356 (whole genome sequencing, targeted proteomics, ROSMAP AMP‐AD), the Illinois Department of Public Health (ROSMAP), and the Translational Genomics Research Institute (genomic). Additional phenotypic data can be requested at www.radc.rush.edu . Study data were provided through NIA grant 3R01AG046171‐02S2 awarded to Rima Kaddurah‐Daouk at Duke University, based on specimens provided by the Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, where data collection was supported through funding by NIA grants P30AG10161, R01AG15819, R01AG17917, R01AG30146, R01AG36836, U01AG32984, U01AG46152, the Illinois Department of Public Health, and the Translational Genomics Research Institute. Funding Information: Data collection and sharing for this project were funded by the Alzheimer's Disease Neuroimaging Initiative (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. Funding Information: Data collection and sharing for this project were supported by The Dominantly Inherited Alzheimer Network (DIAN, U19AG032438), funded by the National Institute on Aging (NIA), the Alzheimer's Association (SG‐20‐690363‐DIAN), the German Center for Neurodegenerative Diseases (DZNE), Raul Carrea Institute for Neurological Research (FLENI), Partial support by the Research and Development Grants for Dementia from Japan Agency for Medical Research and Development, AMED, and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), Spanish Institute of Health Carlos III (ISCIII), Canadian Institutes of Health Research (CIHR), Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, and Fonds de Recherche du Québec – Santé. DIAN Study investigators have reviewed this manuscript for scientific content and consistency of data interpretation with previous DIAN Study publications. We acknowledge the altruism of the participants and their families and the contributions of the DIAN research and support staff at each of the participating sites for their contributions to this study. Funding Information: The results published here are in whole or partly based on data obtained from the AD Knowledge Portal ( https://adknowledgeportal.org ). Metabolomics data is provided by the Alzheimer's Disease Metabolomics Consortium (ADMC) and funded wholly or in part by the following grants and supplements: NIA R01AG046171, RF1AG051550, 3U01AG024904‐09S4, RF1AG057452, R01AG059093, RF1AG058942, U01AG061359, U19AG063744, and FNIH: #DAOU16AMPA awarded to Dr. Kaddurah‐Daouk at Duke University in partnership with a large number of academic institutions. As such, the investigators within the ADMC, not listed specifically in this publication's author's list, provided data along with its pre‐processing and prepared it for analysis but did not participate in the analysis or writing of this manuscript. A complete listing of ADMC investigators can be found at: https://sites.duke.edu/adnimetab/team/ . Funding Information: We would like to pay our gratitude and respects to our friend and collaborator, Jorge Bahena. Jorge was a remarkable scientist and respected colleague. He earned his master's in biostatistics from Washington University School of Medicine and passed away in October 2021 as a doctoral student at Vanderbilt University. His valuable contributions to this and many other endeavors will not be forgotten. This work was possible thanks to the following governmental grants from the National Institute of Health: NIA R01AG057777, RO1AG057777‐02S1, K99AG061281, P30AG066444, P01AGO26276, NINDS R01NS118146 (BAB), R01AG044546 (CC), P01AG003991 (CC, JCM), RF1AG053303 (CC), RF1AG058501 (CC), U01AG058922 (CC), and the Chan Zuckerberg Initiative (CZI). OH is an Archer Foundation Research Scientist. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders and Informatics Center (NGI: https://neurogenomics.wustl.edu/ ), and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2023/5
Y1 - 2023/5
N2 - Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.
AB - Introduction: The identification of multiple genetic risk factors for Alzheimer's disease (AD) suggests that many pathways contribute to AD onset and progression. However, the metabolomic and lipidomic profiles in carriers of distinct genetic risk factors are not fully understood. The metabolome can provide a direct image of dysregulated pathways in the brain. Methods: We interrogated metabolomic signatures in the AD brain, including carriers of pathogenic variants in APP, PSEN1, and PSEN2 (autosomal dominant AD; ADAD), APOE ɛ4, and TREM2 risk variant carriers, and sporadic AD (sAD). Results: We identified 133 unique and shared metabolites associated with ADAD, TREM2, and sAD. We identified a signature of 16 metabolites significantly altered between groups and associated with AD duration. Discussion: AD genetic variants show distinct metabolic perturbations. Investigation of these metabolites may provide greater insight into the etiology of AD and its impact on clinical presentation. HIGHLIGHTS: APP/PSEN1/PSEN2 and TREM2 variant carriers show distinct metabolic changes. A total of 133 metabolites were differentially abundant in AD genetic groups. β-citrylglutamate is differentially abundant in autosomal dominant, TREM2, and sporadic AD. A 16-metabolite profile shows differences between Alzheimer's disease (AD) genetic groups. The identified metabolic profile is associated with duration of disease.
KW - APOE
KW - APP
KW - PSEN1
KW - PSEN2
KW - TREM2
KW - autosomal dominant Alzheimer's disease
KW - lipidomics
KW - metabolomics
KW - β-citrylglutamate
UR - http://www.scopus.com/inward/record.url?scp=85149686793&partnerID=8YFLogxK
U2 - 10.1002/alz.12800
DO - 10.1002/alz.12800
M3 - Article
C2 - 36251323
AN - SCOPUS:85149686793
SN - 1552-5260
VL - 19
SP - 1785
EP - 1799
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 5
ER -