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

Abstract 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.