Kwangsik Nho1, Alexandra Kueider-Paisley2, Siamak MahmoudianDehkordi2, Matthias Arnold3, Shannon L Risacher1, Gregory Louie2, Colette Blach4, Rebecca Baillie5, Xianlin Han6, Gabi Kastenmüller7, Wei Jia8, Guoxiang Xie8, Shahzad Ahmad9, Thomas Hankemeier10, Cornelia M van Duijn9, John Q Trojanowski11, Leslie M Shaw11, Michael W Weiner12, P Murali Doraiswamy13, Andrew J Saykin1, Rima Kaddurah-Daouk14. 1. Department of Radiology and Imaging Sciences, Center for Computational Biology and Bioinformatics, and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA. 2. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA. 3. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. 4. Duke Molecular Physiology Institute, Duke University, Durham, NC, USA. 5. Rosa & Co LLC, San Carlos, CA, USA. 6. University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. 7. Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. 8. University of Hawaii Cancer Center, Honolulu, HI, USA. 9. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, the Netherlands. 10. Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, RA Leiden, the Netherlands. 11. Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. 12. Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA, USA. 13. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke Institute of Brain Sciences, Duke University, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA. 14. Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA; Duke Institute of Brain Sciences, Duke University, Durham, NC, USA; Department of Medicine, Duke University, Durham, NC, USA. Electronic address: rima.kaddurahdaouk@duke.edu.
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: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: 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.
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: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET). RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 ("A") and three with CSF p-tau181 ("T") (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy ("N"), respectively (corrected P < .05). DISCUSSION: 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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