Chemometric profiling reveals selective circulating bile acid remodeling in Alzheimer's disease

Bile acids, cholesterol-derived metabolites, have been implicated in Alzheimer's disease (AD), but it remains unclear whether these changes reflect broad concentration differences or selective chemical remodeling of the circulating bile acid pool. This study examined whether circulating bile acid chemistry differs across cognitively normal (CN; n = 243), mild cognitive impairment (MCI; n = 325), and AD (n = 136) participants, with emphasis on conjugation status, primary-secondary transformation, hydrophobicity/polarity balance, sulfation-related chemistry, and chemometric profiles. Analyses were corrected for multiple comparisons using the FDR method. The results demonstrated that AD participants exhibited selective alterations in circulating bile acid chemistry. Specifically, the conjugated bile acids glycochenodeoxycholic acid (GCDCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA) were significantly elevated in AD, whereas unconjugated bile acids, glycoursodeoxycholic acid (GUDCA), and glycolithocholic acid sulfate (GLCAS) did not differ significantly after FDR correction. Chemistry-derived indices further indicated higher total conjugated bile acids, glycine- and taurine-conjugated bile acid indices, secondary-derived bile acid burden, conjugated/unconjugated ratio, secondary/primary ratio, and hydrophobic/hydrophilic ratio in AD. In contrast, the sulfated/hydrophobic ratio was lower, suggesting a relatively reduced contribution of sulfated bile acids compared with the hydrophobic component. Compositional log-ratio analyses supported a shift toward conjugated, secondary-derived, and hydrophobic bile acid chemistry, while chemical-chemical correlation analyses revealed stronger coupling among conjugation, secondary transformation, hydrophobicity, and sulfation-related indices in AD. Overall, AD was associated with structured bile acid remodeling, mainly involving conjugated, secondary-derived, and hydrophobic domains. Future mechanistic studies are needed to clarify the biological basis of these bile acid alterations.