Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease.
ABCA1
Alzheimer's disease
CPT1A
acylcarnitines
adiponectin
amino acids
genetic
metabolomics
multiscale metabolite co-expression network
risk factors
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
revised:
14
04
2021
received:
28
07
2020
accepted:
17
04
2021
pubmed:
11
11
2021
medline:
9
6
2022
entrez:
10
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34757660
doi: 10.1002/alz.12468
pmc: PMC9085975
mid: NIHMS1733353
doi:
Substances chimiques
Amino Acids
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1260-1278Subventions
Organisme : NIA NIH HHS
ID : RF1 AG057440
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG021886
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG054014
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG017917
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG063744
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG068030
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG059093
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061359
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG057452
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG058635
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG046171
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046152
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG061356
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG052411
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG032984
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG030146
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046170
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG057907
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG024904
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG059319
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG024904
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010161
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG058655
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG058942
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG051550
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062355
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG036836
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG015819
Pays : United States
Informations de copyright
© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
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