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Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome.

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Date
2018-10-08
Authors
MahmoudianDehkordi, Siamak
Arnold, Matthias
Nho, Kwangsik
Ahmad, Shahzad
Jia, Wei
Xie, Guoxiang
Louie, Gregory
Kueider-Paisley, Alexandra
Moseley, M Arthur
Thompson, J Will
St John Williams, Lisa
Tenenbaum, Jessica D
Blach, Colette
Baillie, Rebecca
Han, Xianlin
Bhattacharyya, Sudeepa
Toledo, Jon B
Schafferer, Simon
Klein, Sebastian
Koal, Therese
Risacher, Shannon L
Kling, Mitchel Allan
Motsinger-Reif, Alison
Rotroff, Daniel M
Jack, John
Hankemeier, Thomas
Bennett, David A
De Jager, Philip L
Trojanowski, John Q
Shaw, Leslie M
Weiner, Michael W
Doraiswamy, P Murali
van Duijn, Cornelia M
Saykin, Andrew J
Kastenmüller, Gabi
Kaddurah-Daouk, Rima
Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
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Abstract
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 7α-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.
Type
Journal article
Subject
Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
Permalink
https://hdl.handle.net/10161/17842
Published Version (Please cite this version)
10.1016/j.jalz.2018.07.217
Publication Info
MahmoudianDehkordi, Siamak; Arnold, Matthias; Nho, Kwangsik; Ahmad, Shahzad; Jia, Wei; Xie, Guoxiang; ... Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium (2018). Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome. Alzheimer's & dementia : the journal of the Alzheimer's Association. 10.1016/j.jalz.2018.07.217. Retrieved from https://hdl.handle.net/10161/17842.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Arnold

Matthias Arnold

Adjunct Associate Professor in the Department of Psychiatry and Behavioral Sciences
Doraiswamy

P. Murali Doraiswamy

Professor of Psychiatry and Behavioral Sciences
Murali Doraiswamy MBBS FRCP is Professor of Psychiatry and Professor in Medicine at Duke University School of Medicine where he is a highly cited physician scientist at the Duke Institute for Brain Sciences.  He is also a Senior Fellow at the Duke Center for the Study of Aging and an Affiliate Faculty at the Duke Center for Precision Medicine and Applied Genomics as well as the Duke Microbiome Center.  He directs a clinical trials unit that has been involved in the development of ma
Kaddurah-Daouk

Rima Fathi Kaddurah-Daouk

Professor in Psychiatry and Behavioral Sciences
Overall Research Goals: My research interest over the past decade has focused on scaling up biochemical knowledge for gaining a deeper understanding of the molecular basis of neurodegenerative and neuropsychiatric disorders and finding ways to optimize their treatment. I have also made seminal contributions to the development of the metabolomics field and applications of metabolomics for the study of drug effects, establishing foundations for “Pharmacometabolomi
Moseley

Martin Arthur Moseley III

Adjunct Professor in the Department of Cell Biology
Tenenbaum

Jessica Dale Tenenbaum

Associate Professor of Biostatistics & Bioinformatics
Dr. Tenenbaum is a faculty member in the Division of Translational Biomedical Informatics in the Department of Biostatistics and Bioinformatics. Her primary research interests are  1. Informatics to enable precision medicine; 2. Mental health informatics; 3. Infrastructure and standards to enable research collaboration and integrative data analysis; and 4. Ethical, legal, and social issues that arise in translational research, direct to consumer genetic testing, and data sharing. Cu
Thompson

J. Will Thompson

Adjunct Assistant Professor in the Department of Pharmacology & Cancer Biology
Dr. Thompson's research focuses on the development and deployment of proteomics and metabolomics mass spectrometry techniques for the analysis of biological systems. He served as the Assistant Director of the Proteomics and Metabolomics Shared Resource in the Duke School of Medicine from 2007-2021. He currently maintains collaborations in metabolomics and proteomics research at Duke, and develops new tools for chemical analysis as a Princi
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