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Alzheimers Dement. 2018 Oct 8. pii: S1552-5260(18)33486-1. doi: 10.1016/j.jalz.2018.07.217. [Epub ahead of print]

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

Author information

1
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA.
2
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
3
Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
4
Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands.
5
University of Hawaii Cancer Center, Honolulu, HI, USA; Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
6
University of Hawaii Cancer Center, Honolulu, HI, USA.
7
Duke Proteomics and Metabolomics Shared Resource, Center for Genomic and Computational Biology, Durham, NC, USA.
8
Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA.
9
Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
10
Rosa & Co LLC, San Carlos, CA, USA.
11
University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
12
Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
13
Department of Neurology, Houston Methodist Hospital, Houston, TX, USA.
14
BIOCRATES Life Sciences AG, Innsbruck, Austria.
15
Behavioral Health Service, Crescenz VA Medical Center and Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
16
Bioinformatics Research Center, Department of Statistics, North Carolina State University, Raleigh, NC, USA.
17
Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, RA Leiden, The Netherlands.
18
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
19
Columbia University College of Physicians and Surgeons Department of Neurology, Center for Translational & Computational Neuroimmunology, New York, NY, USA.
20
Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
21
Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA, USA.
22
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke Institute of Brain Sciences, Duke University, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA.
23
Department of Radiology and Imaging Sciences and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: asaykin@iupui.edu.
24
Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. Electronic address: g.kastenmueller@helmholtz-muenchen.de.
25
Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke Institute of Brain Sciences, Duke University, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA. Electronic address: lisa.howerton@duke.edu.

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.

KEYWORDS:

Alzheimer's disease; Atlas for Alzheimer; Genetic variants; Gut microbiome; Gut-liver-brain axis; Immunity; Inflammation; Lipidomics; Metabolome; Metabolomics

PMID:
30337151
DOI:
10.1016/j.jalz.2018.07.217
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