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Horgusluoglu, E.* ; Neff, R.* ; Song, W.M.* ; Wang, M.* ; Wang, Q.* ; Arnold, M. ; Krumsiek, J.* ; Galindo-Prieto, B.* ; Ming, C.* ; Nho, K.* ; Kastenmüller, G. ; Han, X.* ; Baillie, R.* ; Zeng, Q.* ; Andrews, S.* ; Cheng, H.* ; Hao, K.* ; Goate, A.* ; Bennett, D.A.* ; Saykin, A.J.* ; Kaddurah-Daouk, R.* ; Zhang, B.*

Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease.

Alzheimers Dement., DOI: 10.1002/alz.12468 (2021)
Verlagsversion DOI
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Metabolites, the biochemical products of the cellular process, can be used to measure alterations in biochemical pathways related to the pathogenesis of Alzheimer's disease (AD). However, the relationships between systemic abnormalities in metabolism and the pathogenesis of AD are poorly understood. In this study, we aim to identify AD-specific metabolomic changes and their potential upstream genetic and transcriptional regulators through an integrative systems biology framework for analyzing genetic, transcriptomic, metabolomic, and proteomic data in AD. Metabolite co-expression network analysis of the blood metabolomic data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) shows short-chain acylcarnitines/amino acids and medium/long-chain acylcarnitines are most associated with AD clinical outcomes, including episodic memory scores and disease severity. Integration of the gene expression data in both the blood from the ADNI and the brain from the Accelerating Medicines Partnership Alzheimer's Disease (AMP-AD) program reveals ABCA1 and CPT1A are involved in the regulation of acylcarnitines and amino acids in AD. Gene co-expression network analysis of the AMP-AD brain RNA-seq data suggests the CPT1A- and ABCA1-centered subnetworks are associated with neuronal system and immune response, respectively. Increased ABCA1 gene expression and adiponectin protein, a regulator of ABCA1, correspond to decreased short-chain acylcarnitines and amines in AD in the ADNI. In summary, our integrated analysis of large-scale multiomics data in AD systematically identifies novel metabolites and their potential regulators in AD and the findings pave a way for not only developing sensitive and specific diagnostic biomarkers for AD but also identifying novel molecular mechanisms of AD pathogenesis.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Abca1 ; Alzheimer's Disease ; Cpt1a ; Acylcarnitines ; Adiponectin ; Amino Acids ; Genetic ; Metabolomics ; Multiscale Metabolite Co-expression Network ; Risk Factors; Binding Cassette Transporters; Cellular Cholesterol Efflux; Polygenic Hazard Score; Abca1 Expression; Rush Memory; Apoa-i; Adiponectin; Profiles; Cells; Model
ISSN (print) / ISBN 1552-5260
e-ISSN 1552-5279
Verlag Elsevier
Verlagsort New York, NY [u.a.]
Begutachtungsstatus Peer reviewed
Förderungen FNIH
Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health)
DOD ADNI (Department of Defense)
National Institute on Aging
National Institute of Biomedical Imaging and Bioengineering
AbbVie
National Institutes of Health (NIH)/National Institute on Aging
National Institute on Aging (NIA)
NIA
Alzheimer's Association
Alzheimer's Drug Discovery Foundation
Araclon Biotech
Lumosity
Lundbeck
Merck Co., Inc.
Meso Scale Diagnostics, LLC
NeuroRx Research
Neurotrack Technologies
Novartis Pharmaceuticals Corporation
Pfizer Inc.
Piramal Imaging
Servier
Takeda Pharmaceutical Company
Transition Therapeutics
Canadian Institutes of Health Research
Illinois Department of Public Health
Johnson & Johnson Pharmaceutical Research & Development LLC
Janssen Alzheimer Immunotherapy Research & Development, LLC
BioClinica, Inc.
Biogen
Bristol-Myers Squibb Company
CereSpir, Inc.
Cogstate
Eisai Inc.
Elan Pharmaceuticals, Inc.
Eli Lilly and Company
F. Hoffmann-La Roche Ltd
EuroImmun
Genentech, Inc.
Fujirebio
GE Healthcare
IXICO Ltd.
Translational Genomics Research Institute