Causal effects of long-term air pollution exposure on age-independent longitudinal hippocampal atrophy: A Mendelian...

Given the established association between air pollution and central nervous system disorders, particularly the well-characterized link between hippocampal volume and neurodegenerative pathologies, this study aimed to elucidate the causal impact of ambient air pollutants on hippocampal volume changes over time. We employed a two-sample Mendelian randomization (MR) method to analyze genome-wide association study data on longitudinal hippocampal volume changes from publicly available databases, as well as air pollution data. The primary analytical approach used was an inverse variance-weighted method with a multiplicative random-effects model. This was complemented by a sensitivity analysis to verify the robustness of the findings. The MR analysis provided evidence for a causal effect of long-term nitrogen oxide (NOx) exposure on hippocampal atrophy, showing an acceleration of - 90.76 mm³/year (95 % confidence interval: - 149.46 to - 32.07; p = 0.002) per 15.53 μg/m³ increase in ambient concentration. No statistically significant relationships were observed between hippocampal volume trajectories and exposure to particulate matter (PM_2.5) (β = - 5.69, p = 0.71), PMcoarse (PM_2.5-10; β = - 44.11, p = 0.17), PM₁₀ (β = - 17.41, p = 0.41), or nitrogen dioxide (NO₂) (β = - 52.96, p = 0.07). Sensitivity analyses confirmed the absence of detectable horizontal pleiotropy or heterogeneity, supporting the validity of the instrumental variables. This MR study provided novel genetic evidence that chronic exposure to airborne NOx contributes to progressive hippocampal volume loss, highlighting its potential role as a modifiable risk factor of neurodegeneration.