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

Kwangsik Nho, Alexandra Kueider-Paisley, Siamak MahmoudianDehkordi, Matthias Arnold, Shannon L. Risacher, Gregory Louie, Colette Blach, Rebecca Baillie, Xianlin Han, Gabi Kastenmüller, Wei Jia, Guoxiang Xie, Shahzad Ahmad, Thomas Hankemeier, Cornelia M. van Duijn, John Q. Trojanowski, Leslie M. Shaw, Michael W. Weiner, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, for the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
doi: https://doi.org/10.1101/284141
Kwangsik Nho
1Department 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
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Alexandra Kueider-Paisley
2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
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Siamak MahmoudianDehkordi
2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
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Matthias Arnold
2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
3Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
4German Center for Diabetes Research (DZD), Neuherberg, Germany
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Shannon L. Risacher
1Department 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
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Gregory Louie
2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
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Colette Blach
5Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
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Rebecca Baillie
6Rosa & Co LLC, San Carlos, CA, USA
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Xianlin Han
7University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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Gabi Kastenmüller
3Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
4German Center for Diabetes Research (DZD), Neuherberg, Germany
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Wei Jia
8University of Hawaii Cancer Center, Honolulu, Hawaii, USA
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Guoxiang Xie
8University of Hawaii Cancer Center, Honolulu, Hawaii, USA
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Shahzad Ahmad
9Erasmus Medical Centre, Rotterdam, the Netherlands
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Thomas Hankemeier
10Division of Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, the Netherlands
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Cornelia M. van Duijn
9Erasmus Medical Centre, Rotterdam, the Netherlands
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John Q. Trojanowski
11Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Leslie M. Shaw
11Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Michael W. Weiner
12Center for Imaging of Neurodegenerative Diseases, Department of Radiology, San Francisco VA Medical Center/University of California San Francisco, San Francisco, CA
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P. Murali Doraiswamy
2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
13Duke Institute of Brain Sciences, Duke University, Durham, NC, USA
14Department of Medicine, Duke University, Durham, NC, USA
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Andrew J. Saykin
1Department 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
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  • For correspondence: rima.kaddurahdaouk@duke.edu
Rima Kaddurah-Daouk
2Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA
13Duke Institute of Brain Sciences, Duke University, Durham, NC, USA
14Department of Medicine, Duke University, Durham, NC, USA
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  • For correspondence: rima.kaddurahdaouk@duke.edu
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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

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 18, 2018.
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Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers
Kwangsik Nho, Alexandra Kueider-Paisley, Siamak MahmoudianDehkordi, Matthias Arnold, Shannon L. Risacher, Gregory Louie, Colette Blach, Rebecca Baillie, Xianlin Han, Gabi Kastenmüller, Wei Jia, Guoxiang Xie, Shahzad Ahmad, Thomas Hankemeier, Cornelia M. van Duijn, John Q. Trojanowski, Leslie M. Shaw, Michael W. Weiner, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, for the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
bioRxiv 284141; doi: https://doi.org/10.1101/284141
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Altered Bile Acid Profile in Mild Cognitive Impairment and Alzheimer’s Disease: Relationship to Neuroimaging and CSF Biomarkers
Kwangsik Nho, Alexandra Kueider-Paisley, Siamak MahmoudianDehkordi, Matthias Arnold, Shannon L. Risacher, Gregory Louie, Colette Blach, Rebecca Baillie, Xianlin Han, Gabi Kastenmüller, Wei Jia, Guoxiang Xie, Shahzad Ahmad, Thomas Hankemeier, Cornelia M. van Duijn, John Q. Trojanowski, Leslie M. Shaw, Michael W. Weiner, P. Murali Doraiswamy, Andrew J. Saykin, Rima Kaddurah-Daouk, for the Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium
bioRxiv 284141; doi: https://doi.org/10.1101/284141

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