Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study

作者：Vijay R. Varma, Youjin Wang, Yang An, Sudhir Varma, Murat Bilgel, Jimit Doshi, Cristina Legido‐Quigley, João Delgado, Anup Mammen Oommen, Jackson A. Roberts, Dean F. Wong, Christos Davatzikos, Susan M. Resnick, Juan C. Troncoso, Olga Pletniková, Richard O’Brien, Eelko Hak, Brenda N Baak, Ruth M. Pfeiffer, Priyanka Baloni, Siamak Mohmoudiandehkordi, Kwangsik Nho, Rima Kaddurah‐Daouk, David A. Bennett, Shahinaz M. Gadalla, Madhav Thambisetty · 发表于：PLoS Medicine · 年份：2021 · DOI：10.1371/journal.pmed.1003615 · 被引用次数：101 · 研究领域：Drug Transport and Resistance Mechanisms、Cholesterol and Lipid Metabolism、Alzheimer's disease research and treatments

BACKGROUND: While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. METHODS AND FINDINGS: We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an ...