Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study
Vijay R Varma1, Youjin Wang2, Yang An3
1Clinical and Translational Neuroscience Section, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, Maryland, United States of America.
Plos Medicine
|May 27, 2021
Summary
Lower bile acid (BA) levels in men correlate with dementia markers. Bile acid sequestrant use may increase vascular dementia risk in men, suggesting a link between cholesterol metabolism and brain health.
Area of Science:
- Neuroscience
- Metabolomics
- Epidemiology
Background:
- Hypercholesterolemia may accelerate Alzheimer disease (AD) and vascular dementia (VaD).
- Mechanisms linking cholesterol metabolism to dementia are not fully understood.
- This study investigates cholesterol catabolism via bile acids (BAs) in dementia pathogenesis.
Purpose of the Study:
- To examine the role of primary bile acids (cholic acid, chenodeoxycholic acid) and their precursor (7α-hydroxycholesterol) in dementia.
- To assess the association between serum BA markers and neuroimaging indicators of dementia.
- To evaluate the impact of bile acid sequestrants (BAS) on dementia risk.
Main Methods:
- Serum concentrations of 7α-hydroxycholesterol, cholic acid, and chenodeoxycholic acid were measured.
- Associations with brain amyloid, white matter lesions, and atrophy were analyzed using linear regression and mixed-effects models in the BLSA and ADNI cohorts.
- Dementia risk associated with BAS use was assessed using the CPRD dataset.
- Brain tissue concentrations of bile acids and gene expression of their receptors were analyzed in AD and control samples.
Main Results:
- Lower serum levels of 7α-hydroxycholesterol, cholic acid, and chenodeoxycholic acid were linked to increased brain amyloid deposition, white matter lesions, and brain atrophy, particularly in males.
- Bile acid sequestrant use showed no significant association with overall dementia risk but was linked to a higher risk of vascular dementia in males.
- Brain tissue analysis revealed marginally higher cholic acid and chenodeoxycholic acid levels in AD samples, with sex-specific alterations in BA receptor gene expression.
Conclusions:
- Dysregulation of cholesterol catabolism, specifically bile acid metabolism, is implicated in dementia pathogenesis.
- Lower serum BA concentrations in males are associated with neuroimaging markers of dementia.
- Altered BA signaling pathways in the brain may represent a novel mechanism contributing to dementia risk.
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