Proton pump inhibitors and risk of Parkinson's disease: A systematic review and meta-analysis

Parkinson's disease is a progressive neurodegenerative disorder. We assessed whether proton pump inhibitor (PPI) use is associated with PD risk through a systematic review and meta-analysis of observational studies, exploring heterogeneity and confounding. We searched PubMed, Web of Science, Scopus, and the Cochrane Library to September 2025 for cohort and case-control studies. Study quality was evaluated using the Newcastle-Ottawa Scale, and certainty was assessed using GRADE. Random-effects models pooled ORs; prespecified subgroup analyses examined study design, geography, and adjustment for Helicobacter pylori and H₂-blocker use. Six studies from four countries, including 344,580 participants, met the inclusion criteria. Main analysis showed that PPI use was associated with an increased risk of PD (OR = 1.14; 95% CI, 1.07-1.22; P < 0.001). Sensitivity analysis excluding one heterogeneous study reduced I2 to 0% with a slightly lower estimate (OR = 1.09; 95% CI, 1.06-1.13). Subgroup analyses confirmed increased PD risk across both case-control and cohort studies, with stronger effects in cohorts. Geographically, the association was significant in studies from Asia and Europe but not observed in the U.S. Elevated risks persisted when adjusting for H. pylori infection, eradication therapy, and H₂-blocker use. Overall GRADE certainty was low, affected by heterogeneity, missing confounder adjustment, and imprecision. Current evidence suggests a modest association between PPI use and PD, consistent across several analyses but with regional differences. Given their widespread use, further large-scale prospective studies with longer follow-up and careful adjustment for confounders are needed to clarify causality and strengthen the certainty of evidence.