Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1260-1278 |
| Number of pages | 19 |
| Journal | Alzheimer's and Dementia |
| Volume | 18 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2022 |
Keywords
- ABCA1
- Alzheimer's disease
- CPT1A
- acylcarnitines
- adiponectin
- amino acids
- genetic
- metabolomics
- multiscale metabolite co-expression network
- risk factors
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In: Alzheimer's and Dementia, Vol. 18, No. 6, 06.2022, p. 1260-1278.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Integrative metabolomics-genomics approach reveals key metabolic pathways and regulators of Alzheimer's disease
AU - for the Alzheimer's Disease Neuroimaging Initiative (ADNI)
AU - the Alzheimer Disease Metabolomics Consortium
AU - Horgusluoglu, Emrin
AU - Neff, Ryan
AU - Song, Won Min
AU - Wang, Minghui
AU - Wang, Qian
AU - Arnold, Matthias
AU - Krumsiek, Jan
AU - Galindo-Prieto, Beatriz
AU - Ming, Chen
AU - Nho, Kwangsik
AU - Kastenmüller, Gabi
AU - Han, Xianlin
AU - Baillie, Rebecca
AU - Zeng, Qi
AU - Andrews, Shea
AU - Cheng, Haoxiang
AU - Hao, Ke
AU - Goate, Alison
AU - Bennett, David A.
AU - Saykin, Andrew J.
AU - Kaddurah-Daouk, Rima
AU - Zhang, Bin
N1 - Funding Information: This work was supported in parts by grants from the National Institutes of Health (NIH)/National Institute on Aging (U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, R01AG068030, U01AG052411, R01AG062355, U01AG058635). The brain transcriptomic data from the MSBB, ROS/MAP, and Mayo cohorts are available via the AD Knowledge Portal (https://adknowledgeportal.synapse.org). The AD Knowledge Portal is a platform for accessing data, analyses, and tools generated by the Accelerating Medicines Partnership (AMP-AD) Target Discovery Program and other National Institute on Aging (NIA)-supported programs to enable open-science practices and accelerate translational learning. Data are available for general research use according to the following requirements for data access and data attribution (https://adknowledgeportal.synapse.org/#/DataAccess/Instructions). Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.Ioni.usc.edu). The investigators within the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.Ioni.usc.edu) 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 are provided by the Alzheimer's Disease Metabolomics Consortium (ADMC) and funded wholly or in part by the following grants and supplements thereto: NIA R01AG046171, RF1AG051550, 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 but did not participate in analysis or writing of this manuscript. A complete listing of ADMC investigators can be found at: https://sites.duke.edu/adnimetab/team/. Data were generated by the Duke Metabolomics and Proteomics Shared Resource using protocols published previously for blood samples (Toledo et al., https://doi.org/10.1016/j.jalz.2017.01.020; St. John-Williams et al., https://doi.org/10.1038/sdata.2017.140; Arnold et al., https://doi.org/10.1038/s41467-020-14959-w). Data collection and sharing for this project was 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.” Data was generated by the Duke Metabolomics and Proteomics Shared Resource using protocols published previously for blood samples (Toledo et al., https://doi.org/10.1016/j.jalz.2017.01.020; St. John-Williams et al., https://doi.org/10.1038/sdata.2017.140; Arnold et al., https://doi.org/10.1038/s41467-020-14959-w); a custom protocol developed for this study by the Duke shared resource for the brain samples can be found at (https://www.synapse.org/#!Synapse:syn10235609). Data on GCTOF and Lipidomics datasets were generated at UC Davis, a member of ADMC. Protocols for data generation are described at: (https://doi.org/10.1038/sdata.2018.263). For ROS/MAP: “The results published here are in whole or in part based on data obtained from the AMP-AD Knowledge Portal (https://doi.org/10.7303/syn2580853). 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, U01AG61356, the Illinois Department of Public Health, and the Translational Genomics Research Institute.” For all acknowledgement related to the source of the samples other than ROS/MAP refer text found in the AMP-AD Knowledge Portal: (https://adknowledgeportal.synapse.org/#/DataAccess/AcknowledgementStatements). Funding Information: This work was supported in parts by grants from the National Institutes of Health (NIH)/National Institute on Aging (U01AG046170, RF1AG054014, RF1AG057440, R01AG057907, R01AG068030, U01AG052411, R01AG062355, U01AG058635). The brain transcriptomic data from the MSBB, ROS/MAP, and Mayo cohorts are available via the AD Knowledge Portal ( https://adknowledgeportal.synapse.org ). The AD Knowledge Portal is a platform for accessing data, analyses, and tools generated by the Accelerating Medicines Partnership (AMP‐AD) Target Discovery Program and other National Institute on Aging (NIA)‐supported programs to enable open‐science practices and accelerate translational learning. Data are available for general research use according to the following requirements for data access and data attribution ( https://adknowledgeportal.synapse.org/#/DataAccess/Instructions ). Funding Information: Alzheimer's Disease Neuroimaging Initiative (ADNI) database ( adni.Ioni.usc.edu ). The investigators within the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (adni.Ioni.usc.edu) 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 are provided by the Alzheimer's Disease Metabolomics Consortium (ADMC) and funded wholly or in part by the following grants and supplements thereto: NIA R01AG046171, RF1AG051550, 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 but did not participate in analysis or writing of this manuscript. A complete listing of ADMC investigators can be found at: https://sites.duke.edu/adnimetab/team/ . Data were generated by the Duke Metabolomics and Proteomics Shared Resource using protocols published previously for blood samples (Toledo et al., https://doi.org/10.1016/j.jalz.2017.01.020 ; St. John‐Williams et al., https://doi.org/10.1038/sdata.2017.140 ; Arnold et al., https://doi.org/10.1038/s41467‐020‐14959‐w ). Data collection and sharing for this project was 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.” Publisher Copyright: © 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
KW - ABCA1
KW - Alzheimer's disease
KW - CPT1A
KW - acylcarnitines
KW - adiponectin
KW - amino acids
KW - genetic
KW - metabolomics
KW - multiscale metabolite co-expression network
KW - risk factors
UR - http://www.scopus.com/inward/record.url?scp=85118949527&partnerID=8YFLogxK
U2 - 10.1002/alz.12468
DO - 10.1002/alz.12468
M3 - Article
C2 - 34757660
AN - SCOPUS:85118949527
SN - 1552-5260
VL - 18
SP - 1260
EP - 1278
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 6
ER -