Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

Siamak MahmoudianDehkordi; Matthias Arnold; Kwangsik T. Nho; Shahzad Ahmad; Wei Ping Jia; Guoxiang Xie; Gregory Louie; Alexandra Kueider‐Paisley; Martin Arthur Moseley; J. Will Thompson; Lisa St John Williams; Jessica D. Tenenbaum; Colette Blach; Rebecca Baillie; Xianlin Han; Sudeepa Bhattacharyya; Jon B. Toledo; Simon Schafferer; Sebastian Klein; Therese Koal; Shannon L. Risacher; Mitchel A. Kling; Alison A. Motsinger‐Reif; Daniel Miller Rotroff; John Jack; Thomas Hankemeier; David Alan Bennett; Philip L. De Jager; John Q. Trojanowski; Leslie M. J. Shaw

doi:10.1016/j.jalz.2018.07.217

NeuroscienceAlzheimer s & DementiaOct 15, 2018

Peer-reviewed journal article

Altered Bile Acid Profile Associates with Cognitive Impairment in Alzheimer’s Disease – An Emerging Role for Gut Microbiome

Siamak MahmoudianDehkordi iD, Matthias Arnold iD, Kwangsik T. Nho iD, Shahzad Ahmad iD, Wei Ping Jia iD, Guoxiang Xie iD, Gregory Louie iD, Alexandra Kueider‐Paisley iD, Martin Arthur Moseley iD, J. Will Thompson iD, Lisa St John Williams, Jessica D. Tenenbaum iD, Colette Blach iD, Rebecca Baillie iD, Xianlin Han iD, Sudeepa Bhattacharyya iD, Jon B. Toledo iD, Simon Schafferer, Sebastian Klein iD, Therese Koal, Shannon L. Risacher iD, Mitchel A. Kling, Alison A. Motsinger‐Reif iD, Daniel Miller Rotroff iD, John Jack, , Rima F Kaddurah-Daouk iD

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Abstract

IntroductionIncreasing evidence suggests a role for the gut microbiome in central nervous system disorders and specific role for the gut-brain axis in neurodegeneration. Bile acids (BA), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer disease (AD).\n\nMethodsSerum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1,464 subjects including 370 cognitively normal older adults (CN), 284 with early mild cognitive impairment (MCI), 505 with late MCI, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for cofounders and multiple testing.\n\nResultsIn AD compared to CN, we observed significantly lower serum concentrations of a primary BA (cholic acid CA) and increased levels of the bacterially produced, secondary BA, deoxycholic acid (DCA), and its glycine and taurine conjugated forms. An increased ratio of DCA:CA, which reflects 7-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response related genes implicated in AD showed associations with BA profiles.\n\nConclusionWe report for the first time an association between altered BA profile, genetic variants implicated in AD and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut liver brain axis in the pathogenesis of AD.