Abstract
Neuropsychiatric disorders constitute an escalating public health challenge worldwide, with growing evidence suggesting that environmental factors like air pollution may contribute substantially. This prospective cohort study investigated the associations between long-term exposure to fine particulate matter (PM(2.5)) and nitrogen oxides (NO(x)) and the progression of eight neuropsychiatric disorders among 502,356 UK Biobank participants. Using multi-state models, we analyzed three distinct trajectory stages: stage 1 (transition from baseline healthy status to PHQ-4-positive mood disorders), stage 2 (transition from baseline to ICD-10-diagnosed disorders), and stage 3 (progression from PHQ-4-positive status to clinical diagnosis). Nonlinear exposure-response relationships were subsequently characterized using restricted cubic spline (RCS) regression models. The findings indicated that exposure to both PM(2.5) and NO(x) per IQR increase was strongly associated with stage 1, with a corresponding hazard ratio of 1.28 (95% CI: 1.27-1.30) and 1.10 (95% CI: 1.09-1.11). Across the three stages, the risk pattern evolved from being broadly significant to one characterized by disease-specific significance. Alzheimer's disease was consistently identified as the condition with the strongest association and highest risk linked to air pollution. Specifically, hazard ratios across stages were as follows: 1.08-1.13 in stage 2 and 1.14-1.20 in stage 3 for PM(2.5); and 1.04-1.05 in stage 2 and 1.05-1.10 in stage 3 for NO(x). Subgroup analyses identified heightened vulnerability in females (particularly subjects with depression, Parkinson's disease, and sleep disorders), younger individuals, and socioeconomically deprived populations. These findings underscore the importance of considering air pollution as a modifiable risk factor in the prevention of neuropsychiatric disorders.