Dichotomous associations of circulating short-chain organic acids with cognitive impairment in older adults: An epidemiological and network analysis study.

BackgroundShort-chain organic acids (SCOAs) may have paradoxical effects on neurocognition, acting as either neuroprotective bioenergetic substrates or potential neurotoxicants. However, the joint effects of SCOA mixtures on cognitive impairment and the mechanisms underlying their divergent associations remain unclear.ObjectiveTo investigate the joint effects of serum SCOAs mixtures on cognitive impairment and elucidate underlying mechanisms.MethodsSerum levels of 11 SCOAs were quantified in 4192 older adults. Logistic regression and Bayesian kernel machine regression (BKMR) were used to assess individual and mixture associations with cognitive impairment. Potential targets were screened from public databases, intersected with cognitive impairment-related genes, and mapped to protein-protein interaction networks. Core targets were validated using four machine learning algorithms. Functional enrichment and molecular docking analyses were performed to explore potential mechanisms.ResultsIn adjusted models, β-hydroxybutyric, butyric, and propionic acids were inversely associated with cognitive impairment, whereas isobutyric and crotonic acids were positively associated. BKMR revealed a non-linear joint effect, with the overall association shifting from positive to negative when the mixture quantile exceeded 0.5; butyric acid showed an inverted U-shaped relationship. Network analysis identified two functional groups: the inverse group centered on GAPDH, AKT1, CASP3, NFKB1, and STAT3 and was enriched in PI3K-Akt and insulin signaling, whereas the positive group centered on ribosomal proteins and HSP90AA1, implicating ribosomal stress and NOD-like receptor signaling.ConclusionsSerum SCOAs showed divergent associations with cognitive impairment. Bioenergetic metabolites were linked to putative neuroprotective signaling, whereas risk-associated metabolites were linked to ribosomal stress signatures.