Abstract
AIMS: To explore the causal relationship between physical activity (PA) and the progression of Parkinson's disease (PD), we conducted a two-sample Mendelian randomization (MR) analysis. METHODS: Genetic variants were obtained from publicly available genome-wide association study (GWAS) summary statistics for PA (N = 377,000), age at onset (N = 28,568), and PD progression (N = 4093). Causal estimates were calculated using the inverse variance weighted (IVW) method, with MR-Egger and weighted median analyses performed to assess the robustness of the results. RESULTS: Genetically predicted accelerometer-based overall acceleration average (OAA) was associated with a reduced risk of constipation in PD progression (OR: 0.60, 95% CI: 0.42-0.86, p = 5.50 × 10(-3)). Moderate-to-vigorous physical activity (MVPA) demonstrated a similar but stronger effect on constipation risk (OR: 0.03, 95% CI: 9.38 × 10(-4)-0.90, p = 0.043). Additionally, OAA showed a protective effect on motor experiences of daily living (OR: 0.84, 95% CI: 0.71-1.00, p = 0.046). No causal effects were identified for vigorous physical activity (VPA) or the fraction of accelerations exceeding 425 milligravities (FAA) on PD progression. CONCLUSION: Our findings suggest a negative causal relationship between PA and PD progression, highlighting the potential role of physical activity in guiding therapeutic strategies for PD management.