Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer’s Disease
Priyanka Baloni, Cory C. Funk, Jingwen Yan, James T. Yurkovich, Alexandra Kueider‐Paisley, Kwangsik Nho, Almut Heinken, Wei Jia, Siamak MahmoudianDehkordi, Gregory Louie, Andrew J. Saykin, Matthias Arnold, Gabi Kastenmüller, William J. Griffiths, Ines Thiele, Rima Kaddurah‐Daouk, Alexandra Kueider‐Paisley, Gregory Louie, P. Murali Doraiswamy, Colette Blach, Arthur Moseley, Paul M. Thompson, Siamak Mahmoudiandehkhordi, Kathleen Welsh-Balmer, Brenda L. Plassman, Andrew J. Saykin, Kwangsik Nho, Gabi Kastenmüller, Matthias Arnold, Sudeepa Bhattacharyya, Xianlin Han, Rebecca Baillie, Oliver Fiehn, Dinesh Kumar Barupal, Peter J. Meikle, Sarkis K. Mazmanian, Mitchel A. Kling, Leslie M. Shaw, John Q. Trojanowski, Jon B. Toledo, Cornelia van Duijin, Thomas Hankemier, Ines Thiele, Almut Heinken, Nathan D. Price, Cory C. Funk, Priyanka Baloni, Wei Jia, David S. Wishart, Roberta Dı́az Brinton, Rui Chang, Lindsay A. Farrer, Rhoda Au, Wendy Qiu, Peter Würtz, Lara M. Mangravite, Jan Krumsiek, John W. Newman, Bin Zhang, Herman Moreno, Rima Kaddurah‐Daouk, Nathan D. Price
Abstract
Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline.