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

Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)76-92
Number of pages17
JournalAlzheimer's and Dementia
Volume15
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Bile Acids and Salts
Alzheimer Disease
Cholic Acid
Deoxycholic Acid
Brain
Serum
Dysbiosis
Bacteria
Gastrointestinal Microbiome
Cognitive Dysfunction
Liver
Taurine
Central Nervous System Diseases
Neuroimaging
Glycine
Cognition
Multicenter Studies
Cholesterol
Genes

Keywords

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

ASJC Scopus subject areas

  • Epidemiology
  • Health Policy
  • Developmental Neuroscience
  • Clinical Neurology
  • Geriatrics and Gerontology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome. / Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium.

In: Alzheimer's and Dementia, Vol. 15, No. 1, 01.01.2019, p. 76-92.

Research output: Contribution to journalArticle

Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium 2019, 'Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome', Alzheimer's and Dementia, vol. 15, no. 1, pp. 76-92. https://doi.org/10.1016/j.jalz.2018.07.217
Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium. / Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome. In: Alzheimer's and Dementia. 2019 ; Vol. 15, No. 1. pp. 76-92.
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AU - MahmoudianDehkordi, Siamak

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AU - Nho, Kwangsik

AU - Ahmad, Shahzad

AU - Jia, Wei

AU - Xie, Guoxiang

AU - Louie, Gregory

AU - Kueider-Paisley, Alexandra

AU - Moseley, M. Arthur

AU - Thompson, J. Will

AU - St John Williams, Lisa

AU - Tenenbaum, Jessica D.

AU - Blach, Colette

AU - Baillie, Rebecca

AU - Han, Xianlin

AU - Bhattacharyya, Sudeepa

AU - Toledo, Jon B.

AU - Schafferer, Simon

AU - Klein, Sebastian

AU - Koal, Therese

AU - Risacher, Shannon L.

AU - Kling, Mitchel Allan

AU - Motsinger-Reif, Alison

AU - Rotroff, Daniel M.

AU - Jack, John

AU - Hankemeier, Thomas

AU - Bennett, David A.

AU - De Jager, Philip L.

AU - Trojanowski, John Q.

AU - Shaw, Leslie M.

AU - Weiner, Michael W.

AU - Doraiswamy, P. Murali

AU - van Duijn, Cornelia M.

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AU - Kastenmüller, Gabi

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AB - 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.

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KW - Genetic variants

KW - Gut microbiome

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KW - Inflammation

KW - Lipidomics

KW - Metabolome

KW - Metabolomics

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