Abstract
IMPORTANCE: Air pollution exposure has been associated with an increased risk of neurodegenerative diseases; however, evidence is limited for motor neuron disease (MND), especially regarding disease progression. OBJECTIVE: To determine whether long-term exposure to air pollution is associated with the risk and prognosis of MND. DESIGN, SETTING, AND PARTICIPANTS: This population-based, nested case-control study used Swedish health register data of incident MND cases diagnosed between 2015 and 2023 with up to 8 years of follow-up. Participants included patients with MND, 5 age- and sex-matched population controls without MND per patient with MND, and full siblings of the patients with MND. Data were analyzed between November 6, 2024, and November 4, 2025. EXPOSURES: Mean yearly concentrations of particulate matters of 2.5 µm or less, 10 µm or less, or 2.5 to 10 µm in diameter (PM2.5, PM10, PM2.5-10) and nitrogen dioxide (NO2) were assessed at the residential address using a spatiotemporal model to approximate accumulated air pollution exposure. MAIN OUTCOME AND MEASURES: Association between air pollution and risk of MND was assessed by comparing cases to both population and sibling controls. Flexible parametric survival models estimated the association between air pollution exposure and the risk of mortality (or use of invasive ventilation) after MND diagnosis (case-only analyses). Based on the rate of decline in the ALS Functional Rating Scale-Revised (ALSFRS-R) score and its subscores after diagnosis, patients were classified into fast (upper 25th percentile) or slow (lower 75th percentile) progression. Logistic regression was used to assess air pollution exposure and the risk of fast progression. RESULTS: The study included 1463 patients with MND, 7310 population controls, and 1768 sibling controls. The mean (SD) age for all patients with MND was 67.3 (11.7) years, and 814 (55.6) were male. In the population comparison, long-term air pollution was associated with an increased risk of MND; per IQR increase in the 10-year average level, the odds ratio was 1.21 (95% CI, 1.09-1.34) for PM2.5, 1.30 (95% CI, 1.19-1.42) for PM2.5-10, 1.29 (95% CI, 1.18-1.42) for PM10, and 1.20 (95% CI, 1.12-1.29) for NO2. A higher level of PM10 or NO2 was associated with a higher hazard of mortality, whereas a higher level of all PMs was associated with faster functional decline, particularly motor and respiratory functions, after MND diagnosis. CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that air pollution, even at relatively low levels typical of Sweden, may contribute both to the risk of developing MND and disease prognosis after MND diagnosis.