Journal
ALZHEIMERS & DEMENTIA
Volume 15, Issue 1, Pages 76-92Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2018.07.217
Keywords
Metabolomics; Metabolome; Lipidomics; Alzheimer's disease; Gut microbiome; Gut-liver-brain axis; Atlas for Alzheimer; Genetic variants; Immunity; Inflammation
Categories
Funding
- National Institute on Aging [P30AG10161, R01AG15819, R01AG17917, U01AG46152, RF1 AG0151550]
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute of Biomedical Imaging and Bioengineering [R01EB022574]
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- Biogen
- Bristol-Myers Squibb Company
- CereSpir, Inc.
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd
- Fujirebio
- Johnson & Johnson Pharmaceutical Research & Development LLC.
- Meso Scale Diagnostics
- NeuroRx Research
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Takeda Pharmaceutical Company
- Canadian Institutes of Health Research
- ADNI clinical sites in Canada
- Foundation for the National Institutes of Health
- Northern California Institute for Research and Education
- Laboratory for Neuro Imaging at the University of Southern California
- NIA [U01AG024904-09S4, P50NS053488, R01AG19771, P30AG10133, P30AG 10124, K01AG049050, R03AG054936]
- National Library of Medicine [R01LM011360, R00LM011384, R01 LM012535]
- Helmholtz Zentrum
- Indiana Clinical and Translational Science Institute
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- Netherlands Organization of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]
- Genetic Laboratory of the Department of Internal Medicine, Erasmus MC
- Research Institute for Diseases in the Elderly [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]
- NIH [U01 AG024904, R01 MH 098260, R01 AG 046171, 1RF AG 051550]
- MJFox Foundation
- AbbVie
- BioClinica, Inc.
- Genentech, Inc.
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC.
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC.
- Neurotrack Technologies
- Piramal Imaging
- Servier
- Transition Therapeutics
- Indiana University-IU Health Strategic Neuroscience Research Initiative
- Erasmus Medical Center, Rotterdam
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- European Commission (DG XII)
- Springer
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB022574] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [ZIAES103335] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH098260] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P50NS053488] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [RF1AG057452, U19AG024904, K01AG049050, P30AG010133, U01AG046152, R03AG054936, R01AG048015, P30AG010124, R01AG015819, R01AG017917, P30AG010161, RF1AG051550, R01AG046171, R01AG019771] Funding Source: NIH RePORTER
- NATIONAL LIBRARY OF MEDICINE [R01LM012535] Funding Source: NIH RePORTER
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Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. Results: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid: CA, which reflects 7 alpha-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles. Discussion: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.
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