Metabolomic profiling identifies signatures and biomarkers linking air pollution to dementia risk: a prospective cohort study

Exposure to air pollution has been associated with increased dementia. However, it remains unknown what specific metabolic mechanisms play a role in this relationship. We included 192,300 dementia-free participants from the UK Biobank cohort study. Annual concentrations of air pollution were assessed based on the residential address. Elastic net regression was performed to identify air pollution-related metabolites, and metabolic score was constructed. Cox regression models and covariate balancing generalized propensity scores (CBGPS) regression models were conducted to explore the longitudinal associations between air pollution/metabolic signatures and dementia risk. The underlying mechanisms between air pollution and dementia driven by metabolic signature or specific metabolites were also investigated. A total of 2,592 incident dementia cases were documented. We identified the metabolite profiles in response to air pollution exposure, including 87 metabolites for PM_2.5, 65 metabolites for PM₁₀, 76 metabolites for NO₂, and 71 metabolites for NO_x. The air pollution-related metabolic signatures were associated with increased risk of dementia, with hazard ratios (HR) of 1.17 (95% CI: 1.12, 1.22), 1.06 (95% CI: 1.02, 1.11), 1.16 (95% CI: 1.10, 1.21), and 1.17 (95% CI: 1.12, 1.22) for PM_2.5, PM₁₀, NO₂ and NO_x, respectively. The associations persisted using causal models. Metabolic signatures mediated the associations between air pollution exposure and dementia risk, with mediation proportions ranging from 6.57% to 12.71%. Additionally, we observed that a metabolite known as free cholesterol in medium VLDL (M-VLDL-FC) played a crucial mediating role. Our study provides novel insights into the metabolic mechanisms linking air pollution exposure to dementia risk.