Abstract
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 Alzheimer’s disease (AD) including neuroinflammation and amyloid-β 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.
Footnotes
↵† Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf
Abbreviations:AD: Alzheimer’s disease; ADMC: Alzheimer’s disease Metabolomics Consortium; ADNI: Alzheimer’s Disease Neuroimaging Initiative; APOE: apolipoprotein E; BBB: blood-brain barrier; BA: bile acid; CA: Cholic acid; CDCA: Chenodeoxycholic acid; CN: Cognitively normal older control; DCA: Deoxycholic acid; EMCI: Early mild cognitive impairment; FDR: False discovery rate; FXR: Farnesoid X Receptor; GCA: Glycocholic acid; GCDCA: Glycochenodeoxycholic acid; GDCA: Glycodeoxycholic acid; GLCA: Glycolithocholic acid; GUDCA: Glycoursodeoxycholic acid; ICV: intracranial volume; LCA: Lithocholic acid; LMCI: Late mild cognitive impairment; MCI: Mild cognitive impairment; MRI: magnetic resonance imaging; PET: positron emission tomography; TCA: Taurocholic acid; TCDCA: taurochenodeoxycholic acid; TDCA: Taurodeoxycholic acid; TLCA: Taurolithocholic acid; TMCA: Trimethoxycinnamic acid; TUDCA: Tauroursodeoxycholic acid; UDCA: Ursodeoxycholic acid
