Cumulative proton pump inhibitor exposure and risk of Parkinson’s disease: a nationwide cohort study

Using the Korean National Health Insurance Service–National Sample Cohort database, we evaluated the association between proton pump inhibitor (PPI) exposure and the risk of Parkinson’s disease (PD) among adults aged ≥ 40 years with upper gastrointestinal disorders. PPI exposure during the seven years preceding the index date was assessed by overall use, cumulative duration, and cumulative defined daily dose (cDDD). Inverse probability of treatment weighting (IPTW) and propensity score matching (PSM) were applied, and hazard ratios (HRs) were estimated. Overall PPI use was not significantly associated with PD risk (IPTW HR, 0.95; 95% CI, 0.89–1.02; PSM HR, 0.93; 95% CI, 0.84–1.03). However, higher cumulative exposure was associated with elevated risk estimates. For ≥ 180 days of use, HRs were 2.24 (95% CI, 1.92–2.60) with IPTW and 1.25 (95% CI, 0.91–1.72) with PSM; for ≥ 180 cDDD, the corresponding HRs were 2.20 (95% CI, 1.89–2.57) and 1.32 (95% CI, 1.01–1.null1), respectively. This positive dose-response pattern remained robust across multiple sensitivity analyses, including washout period assessments, although statistical precision varied by matching design. Therefore, these findings suggest a potential association between higher cumulative PPI exposure and an increased risk of PD.