Ursodeoxycholic Acid and Parkinson's Disease Risk: An Emulated Target Trial in UK Electronic Health Records.

BACKGROUND: Ursodeoxycholic acid (UDCA) has shown mitochondrial and neuroprotective effects and has been proposed as a treatment for Parkinson's disease (PD). However, population-level evidence on its effect on PD risk is lacking. OBJECTIVES: To compare the risk of incident PD among UDCA initiators versus matched non-initiators within a hepatobiliary disease population. METHODS: We conducted a cohort study emulating a target trial using UK primary care records linked to hospital and mortality data from 1990 to 2023. Eligible participants were adults aged 45-84 years with hepatobiliary disease and no prior PD diagnosis or antiparkinsonian treatment. The intervention was UDCA initiation versus non-initiation. We emulated 160 sequential trials across 3-month age intervals and matched UDCA initiators 1:3 to non-initiators using propensity scores. The main outcome was incident PD. Cumulative incidence was estimated using pooled logistic regression to derive risk differences (RDs) and risk ratios (RRs) with 95% confidence intervals (CIs). Secondary analyses used alternative outcome definitions, a 3-year onset-anchored definition, and a per-protocol cumulative dose-response analysis. RESULTS: After matching 17,295 UDCA initiators to 51,885 non-initiators, the 15-year risk of PD was 1.70% versus 2.16% (RD -0.46 percentage points [95% CI -0.94 to -0.02]; RR 0.79 [95% CI 0.59 to 0.99]). The onset-anchored analysis gave an RR of 0.69 (95% CI 0.48 to 0.90), and the per-protocol dose-response analysis an RR of 0.74 (95% CI 0.49 to 0.99). CONCLUSIONS: UDCA treatment is associated with a lower risk in PD. These findings require confirmation in randomized controlled trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.