In a cohort of older adults with type 2 diabetes initiating GLP-1 receptor agonists, a genetic score proxying higher systemic GLP1R expression was associated with a 22% lower hazard of incident Parkinson's disease and related disorders (HR 0.78), with consistent sensitivity analyses.

Provides mechanism-anchored genetic support that GLP1R-mediated pathways influence PDRD risk, strengthening rationale for GLP-1RA repurposing and for incorporating GLP1R-expression–based stratification or biomarkers into future Parkinson's prevention and therapeutic trials.

Preclinical and epidemiologic data suggest that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may reduce the risk of Parkinson's disease and related disorders (PDRD), yet clinical trial findings have been mixed, raising the possibility of biologically meaningful heterogeneity. We tested whether interindividual differences in systemic GLP1R expression are associated with PDRD risk among adults with type 2 diabetes initiating GLP-1RAs. We conducted an electronic health record (EHR)-based new-user cohort study in the National Institutes of Health All of Us Research Program, focusing on adults with type 2 diabetes aged 50 years or older who initiated a GLP-1RA between 2005 and 2023 and had no prior PDRD or Alzheimer's disease and related dementias (ADRD). Systemic GLP1R expression was genetically proxied by a 15-variant cis-expression quantitative trait locus (cis-eQTL) genetic risk score dichotomized at the cohort median. Follow-up ended at the earliest of incident PDRD, death, or October 1, 2023. Hazard ratios were estimated using multivariable Cox proportional hazards models adjusting for baseline covariates, and incidence rates and rate differences per 1,000 person-years were estimated using Poisson models. Prespecified sensitivity analyses excluded early outcome events and short drug exposure; an exploratory analysis evaluated incident ADRD. The cohort included 7,039 initiators (3,520 high vs 3,519 low genetic score; mean age 61.7 ± 8.4 years; 59.8% female; mean follow-up 3.8 ± 3.1 years). Compared with the low-score group, the high-score group had a lower hazard of incident PDRD (hazard ratio 0.78; 95% confidence interval 0.62 to 0.98) and a lower incidence rate (rate difference -1.36 per 1,000 person-years; 95% confidence interval -2.51 to -0.20). Associations were consistent across sensitivity analyses. No association was observed for incident ADRD (hazard ratio 1.02; 95% confidence interval 0.81 to 1.28). These findings link a mechanism-anchored genetic proxy for higher systemic GLP1R expression to a lower risk of incident PDRD among GLP-1RA-treated adults with type 2 diabetes. Systemic GLP1R-mediated pathways may be relevant to interindividual differences in observed PDRD risk, and genetic instruments for GLP1R expression may inform hypotheses for future PDRD trial design.