**Background:** Proton pump inhibitors (PPIs) are among the most prescribed drugs worldwide for gastric acid-related disorders. Previous studies have linked PPI use to an increased risk of dementia and Alzheimer's disease, but the relationship between PPIs and Parkinson's disease (PD) was not well understood. Given that gastric ulcer disease and Helicobacter pylori infection have been implicated in PD development, and these conditions are treated with PPIs, the authors aimed to examine whether PPI use is associated with an increased risk of developing clinically verified PD using real-world data from Taiwan's entire population.
**Methods:** This retrospective cohort study used data from the Taiwan National Health Insurance Research Database (NHIRD) and the Longitudinal Health Insurance Database 2000 (LHID 2000), which covers nearly 99% of Taiwan's population. The study included adults aged ≥20 years between January 1, 1999, and December 31, 2011. From 65,350 new PPI users, patients with pre-existing PD, previous H. pylori infection, or age <20 years were excluded, leaving 56,785 PPI users. These were matched 1:1 to 56,785 non-PPI users by age, sex, cohort entry year, and comorbidities (cirrhosis, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, hypertension, coronary artery disease, epilepsy, and cerebrovascular disease). Multivariate analysis was performed using Cox proportional hazards models to estimate the association between PPI use and PD risk. Subgroup analyses stratified by sex, age, and comorbidities were conducted. PPI use was also analyzed by cumulative defined daily doses (cDDDs): <90, 90–180, and ≥180.
**Key Results:** The mean age of PPI users was 47.1 years (SD 14.9), and 51.4% were male. During a median follow-up of 5.0 years, 366 PPI users (0.64%) and 258 controls (0.45%) developed PD. The incidence rate of PD was 1.48-fold higher in PPI users than in non-PPI users (133.2 vs 90.0 per 100,000 person-years). After adjustment, PPI use was independently associated with a significantly increased risk of developing PD (adjusted HR = 1.76; 95% CI 1.48–2.08; P < .001). Age >60 years was the strongest risk factor (adjusted HR = 11.46; 95% CI 9.33–14.09; P < .001). Comorbidities significantly associated with increased PD risk included hypertension (aHR 1.66), chronic kidney disease (aHR 1.71), coronary artery disease (aHR 1.31), COPD (aHR 1.46), cirrhosis (aHR 1.31), and cerebrovascular disease (aHR 1.62). In subgroup analyses, PPI use was significantly associated with PD across nearly all subgroups, including by sex, age, and comorbidities. Notably, even low PPI dosage (cDDDs <90) was associated with increased PD risk (adjusted HR = 2.32; 95% CI 1.90–2.82; P < .001), while higher dosages showed attenuated but still significant associations (cDDDs 90–180: aHR 1.54; cDDDs ≥180: aHR 1.30).
**Clinical Implications:** This large population-based study provides evidence that PPI use is associated with an increased risk of developing Parkinson's disease, with a 76% relative risk increase after adjustment. The authors propose several biological mechanisms that may explain this association: (1) PPI-induced vitamin B12 deficiency leading to elevated homocysteine and methylmalonic acid, which may be neurotoxic to dopaminergic cells; (2) impaired iron absorption causing iron-deficiency anemia, which has been linked to higher PD risk in prior Taiwanese studies and may impair dopamine synthesis; (3) magnesium deficiency from prolonged PPI use, as higher magnesium intake has been associated with reduced PD risk; and (4) small intestinal bacterial overgrowth (SIBO) from gastric acid suppression, which may promote systemic inflammation, disrupt the blood-brain barrier, and mediate neuroinflammation. The authors recommend that clinicians carefully balance the benefits and risks of long-term PPI therapy, especially in older patients, and suggest that vitamin B12 supplementation may be advisable. However, they acknowledge the limitations of retrospective observational studies, including potential residual confounding, and emphasize that randomized prospective clinical trials are needed to establish causality. The study was supported by grant TCRD 103–36 from Hualien Tzu Chi Hospital.