Altered bile acid profile associates with cognitive impairment in Alzheimer's disease—An emerging role for gut microbiome
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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.
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Disturbance in the gut microflora results in increased production of secondary cytotoxic bile acid, mainly deoxycholic acid, which can cross the blood brain barrier and get deposited in the brain leading to apoptosis, generation of reactive oxygen species, inflammation and neurodegeneration.
“Disturbance in the gut microflora results in increased production of secondary cytotoxic bile acid, mainly deoxycholic acid, which can cross the blood brain barrier and get deposited in the brain leading to apoptosis, generation of reactive oxygen species, inflammation and neurodegeneration [21].”
From Recent Advancements in Pathogenesis, Diagnostics and Treatment of Alzheimer’s Disease (2020) · cites this paper as [21]
Studies in AD patients report a consistent pattern of reduced levels of primary bile acids and elevated levels of secondary bile acids.
“Although studies in AD patients have yielded slightly heterogeneous results in BA composition, they have reported a consistent pattern of reduced levels of primary BAs and elevated levels of secondary BAs.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [356]
Secondary bile acids associated with AD and cognitive impairments include DCA, LCA, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid, and taurolithocholic acid.
“Secondary BAs associated with AD and cognitive impairments include DCA, LCA, glycodeoxycholic acid, taurodeoxycholic acid, glycolithocholic acid, and taurolithocholic acid.355–358”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [356]
Secondary BA levels were associated with the progression of AD symptoms from mild to severe, with higher levels of secondary BAs being correlated with worse cognitive function.
“Secondary BA levels were associated with the progression of AD symptoms from mild to severe, with higher levels of secondary BAs being correlated with worse cognitive function [79].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [79]
AD patients have decreased levels of systemic primary BAs and enhanced levels of distinct secondary BAs compared to healthy controls, which are directly correlated with impairments in cognitive functioning and brain glucose mechanism.
“AD patients have been found to demonstrate decreased levels of systemic primary BAs and enhanced levels of distinct secondary BAs (the product of gut microbial metabolism) when compared to healthy controls, which are directly correlated with impairments in cognitive functioning and brain glucose mechanism [79].”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [79]
As bile acid synthesis is crucially dependent on dietary factors, and secondary bile are exclusively generated by certain gut microbes, these findings suggest a possible role of diet and the gut microbiome in the observed alterations in the ratio between primary and secondary BAs.
“As bile acid synthesis is crucially dependent on dietary factors, and as secondary bile are exclusively generated by certain gut microbes, these findings suggest a possible role of diet and the gut microbiome in the observed alterations in the ratio between primary and secondary BAs.”
From Role of diet and its effects on the gut microbiome in the pathophysiology of mental disorders (2022) · cites this paper as [79]
Abnormal bile acid metabolism has been described in neurological diseases, suggesting a role for transformation of bile acids by gut microbiota in Alzheimer's disease development/progression and cognitive decline.
“Recently, abnormal bile acid metabolism was described in neurological diseases, suggesting a role for the transformation of bile acids by gut microbiota as a factor in Alzheimer's disease development/progression and cognitive decline (409, 410).”
From Diet and the Microbiota–Gut–Brain Axis: Sowing the Seeds of Good Mental Health (2021) · cites this paper as [409]
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Comprehensive metabolic profiling of Parkinson’s disease by liquid chromatography-mass spectrometry
Shao, Y., Li, T., Liu, Z., Wang, X., Xu, X., Li, S., Xu, G., & Le, W. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00425-8 · Cited by 226 · see citing works
Diet, inflammation and the gut microbiome: mechanisms for obesity-associated cognitive impairment
Leigh, S.-J., & Morris, M. J. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165767 · Cited by 221 · see citing works
Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
Baloni, P., Funk, C. C., Yan, J., Yurkovich, J. T., Kueider-Paisley, A., Nho, K., Heinken, A., Jia, W., Mahmoudiandehkordi, S., Louie, G., et al. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100138 · Cited by 211 · see citing works
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The biosynthesis, signaling, and neurological functions of bile acids
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Arnold, M., Nho, K., Kueider-Paisley, A., Massaro, T., Huynh, K., Brauner, B., MahmoudianDehkordi, S., Louie, G., Moseley, M. A., Thompson, J. W., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14959-w · Cited by 202 · see citing works
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“Short-chain fatty acids (SCFAs) (38), bile acids (39), and some neurotransmitters such as g-amino butyric acid (GABA) (40) and dopamine (41) were commonly metabolites potentially involved in this communication.”
BackgroundTime to test antibacterial therapy in Alzheimer’s disease
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Self-citationBile acids: a communication channel in the gut-brain axis
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Is Alzheimer’s Disease a Liver Disease of the Brain?
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Bile acids as key modulators of the brain-Gut-Microbiota axis in alzheimer’s disease
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Metabolomic Profiling of Bile Acids in an Experimental Model of Prodromal Parkinson’s Disease
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Nutrition, gut microbiota, and alzheimer’s disease
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[Retracted] A Review of Bile Acid Metabolism and Signaling in Cognitive Dysfunction‐Related Diseases
Weng, Z.-B., Chen, Y.-R., Lv, J.-T., Wang, M.-X., Chen, Z.-Y., Zhou, W., Shen, X.-C., Zhan, L.-B., & Wang, F. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/4289383 · Cited by 32 · see citing works
RetractedReddy, J. S., Heath, L., Linden, A. V., Allen, M., Lopes, K. D. P., Seifar, F., Wang, E., Ma, Y., Poehlman, W. L., Quicksall, Z. S., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.14208 · Cited by 29 · see citing works
Self-citationThe endocannabinoid system: a bridge between alzheimer’s disease and gut microbiota
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- Authors
- MahmoudianDehkordi, S., Arnold, M., Nho, K., Ahmad, S., Jia, W., Xie, G., Louie, G., Kueider‐Paisley, A., Moseley, M. A., Thompson, J. W., St John Williams, L., Tenenbaum, J. D., Blach, C., Baillie, R., Han, X., Bhattacharyya, S., Toledo, J. B., Schafferer, S., Klein, S., Koal, T., Risacher, S. L., Allan Kling, M., Motsinger‐Reif, A., Rotroff, D. M., Jack, J., Hankemeier, T., Bennett, D. A., De Jager, P. L., Trojanowski, J. Q., Shaw, L. M., Weiner, M. W., Doraiswamy, P. M., van Duijn, C. M., Saykin, A. J., Kastenmüller, G., Kaddurah‐Daouk, R., & for the Alzheimer's Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
- Affiliations
- Duke University (US)
- Indiana University Indianapolis (US)
- Erasmus MC (NL)
- Shanghai Jiao Tong University (CN)
- University of Hawaii Cancer Center (US)
- Duke Proteomics and Metabolomics Shared Resource Center for Genomic and Computational Biology Durham NC USA
- Rosa (United States) (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Arkansas for Medical Sciences (US)
- Houston Methodist (US)
- Biocrates Life Sciences (Austria) (AT)
- Behavioral Health Service Crescenz VA Medical Center and Department of Psychiatry Perelman School of Medicine University of Pennsylvania Philadelphia PA USA
- North Carolina State University (US)
- Leiden University (NL)
- Rush University Medical Center (US)
- Columbia University College of Physicians and Surgeons Department of Neurology Center for Translational & Computational Neuroimmunology New York NY USA
- University of Pennsylvania (US)
- San Francisco VA Medical Center (US)
- Department of Epidemiology Erasmus Medical Centre Rotterdam the Netherlands
- Helmholtz Munich (DE)
- Department of Psychiatry and Behavioral Sciences Duke University Durham NC USA
- Corresponding author
- Saykin, Andrew J.
- Kastenmüller, Gabi
- ORCID
- MahmoudianDehkordi, Siamak
- Arnold, Matthias
- Nho, Kwangsik
- Ahmad, Shahzad
- Jia, Wei
- Xie, Guoxiang
- Louie, Gregory
- Kueider‐Paisley, Alexandra
- Moseley, M. Arthur
- Tenenbaum, Jessica D.
- Blach, Colette
- Baillie, Rebecca
- Han, Xianlin
- Bhattacharyya, Sudeepa
- Toledo, Jon B.
- Klein, Sebastian
- Risacher, Shannon L.
- Motsinger‐Reif, Alison
- Rotroff, Daniel M.
- Hankemeier, Thomas
- Bennett, David A.
- Trojanowski, John Q.
- Shaw, Leslie M.
- Weiner, Michael W.
- Doraiswamy, P. Murali
- Saykin, Andrew J.
- Kastenmüller, Gabi
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2018-10-15
- Volume
- 15
- Issue
- 1
- Pages
- 76-92
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC6487485
- OpenAlex
- W2794227656
- Cited by
- 706
- References
- 79
- Citations by year
- 2026: 93 · 2025: 113 · 2024: 126 · 2023: 79 · 2022: 105 · 2021: 87 · 2020: 61 · 2019: 37 · 2018: 4
- FWCI
- 36.97
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-03-21)
- Open access
- green
- doi.org
- Locations
- Alzheimer s & Dementia (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Funders
- National Institute on Aging (R01AG046171, P30AG10161, R01AG15819, R01AG17917, U01AG46152, U01AG024904-09S4, P50NS053488, R01AG19771, P30AG10133, P30AG10124, K01AG049050, R03AG054936)
- National Institutes of Health (U01 AG024904, R01 MH 098260, R01 AG 046171, 1RF AG 051550)
- U.S. National Library of Medicine (R01LM011360, R00LM011384, R01 LM012535)
- National Institute of Biomedical Imaging and Bioengineering (R01EB022574)
- Erasmus Medisch Centrum
- Erasmus Universiteit Rotterdam
- ZonMw
- Directorate-General XII, Science, Research, and Development
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, bile acids
- MeSH terms
- Gastrointestinal Microbiome, Aged, Alzheimer Disease, Bile Acids and Salts, Female, Humans, Liver, Male, Metabolome, Cognitive Dysfunction, Dysbiosis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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