Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer's Disease: Relationship to Neuroimaging and CSF Biomarkers

Introduction: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimers disease (AD) including neuroinflammation and amyloid-beta deposition. Method: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n=1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the A/T/N (Amyloid, Tau and Neurodegeneration) biomarkers for AD: CSF biomarkers, atrophy (MRI), and brain glucose metabolism ([18F]FDG-PET). Results: Of 23 BA and relevant calculated ratios, three BA signatures were associated with CSF Aβ1-42 (A) and three with CSF p-tau181 (T) (corrected p<0.05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy (N), respectively (corrected p<0.05). Conclusion: This is the first study to show serum-based BA metabolites are associated with A/T/N AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.

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