Varma VR, Wang Y, An Y, et al. - While hypercholesterolemia may accelerate Alzheimer disease (AD) and vascular dementia (VaD), there remains uncertainty regarding the mechanisms underlying this association. Researchers aimed at examining if dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was linked with dementia pathogenesis. In this study, first they tested the correlation between serum oxysterols and BAs and neuroimaging markers of dementia. In addition, they examined a large, real-world clinical dataset for the correlation between exposure to bile acid sequestrants (BAS) and risk of dementia. At last, plausible mechanisms underlying these correlations were investigated by ascertaining if primary BAs and mRNA of their receptors were altered in the brain in dementia. Findings revealed higher brain amyloid deposition, faster WML accumulation, and faster brain atrophy, mainly in males, when there were lower serum levels of 7α-hydroxycholesterol (7α-OHC) and primary BAs. In line with this finding, a gender difference was noted in the correlation between use of BAS and risk of VaD. The brain showed detectable primary BAs, and there was alteration in levels of gene expression of BA receptors in AD mainly in males. Overall, cholesterol catabolism and BA synthesis are suggested to have a possible influence on dementia progression through gender-specific effects on signaling pathways in the brain.