This study examined whether interindividual differences in systemic GLP1R expression are associated with the risk of Parkinson’s disease and related disorders (PDRD) among adults with type 2 diabetes who initiated GLP-1 receptor agonist (GLP-1RA) therapy. The investigators used electronic health record data from the National Institutes of Health All of Us Research Program to construct a new-user cohort of GLP-1RA initiators and applied a genetic proxy for systemic GLP1R expression to evaluate associations with incident neurodegenerative outcomes.
The cohort comprised 7,039 adults with type 2 diabetes aged 50 years or older who started a GLP-1RA between 2005 and 2023 and had no prior diagnosis of PDRD or Alzheimer’s disease and related dementias (ADRD). The cohort was split by the median of a genetic score into 3,520 participants in the high genetic score group and 3,519 in the low genetic score group. Mean age at initiation was 61.7 ± 8.4 years; 59.8% of the cohort were female. Mean follow-up was 3.8 ± 3.1 years. Follow-up ended at the earliest of incident PDRD, death, or 1 October 2023.
Systemic GLP1R expression was genetically proxied using a 15-variant cis-expression quantitative trait locus (cis-eQTL) genetic risk score. The score was dichotomized at the cohort median to define participants with higher versus lower genetically predicted systemic GLP1R expression. The genetic instrument anchored the analysis to a biologically plausible mechanism and allowed assessment of whether genetically influenced differences in systemic expression relate to clinical outcomes among GLP-1RA users.
The primary outcome was incident PDRD. An exploratory outcome evaluated incident ADRD. Hazard ratios (HRs) for time-to-event analyses were estimated using multivariable Cox proportional hazards models with adjustment for baseline covariates. Incidence rates and absolute rate differences per 1,000 person-years were estimated using Poisson models. Prespecified sensitivity analyses excluded early outcome events and participants with short drug exposure to assess the robustness of findings.
Compared with the low-score group, the high-score group had a lower hazard of incident PDRD (adjusted HR 0.78; 95% confidence interval [CI] 0.62 to 0.98). In absolute terms, the high genetic score was associated with a lower incidence rate of PDRD, with a rate difference of −1.36 per 1,000 person-years (95% CI −2.51 to −0.20). These results indicate a statistically significant association between genetically proxied higher systemic GLP1R expression and reduced risk of developing PDRD among GLP-1RA initiators with type 2 diabetes.
The reported associations were consistent across prespecified sensitivity analyses that excluded early outcome events and short drug exposures, suggesting robustness to potential reverse causation and to brief exposure periods. An exploratory analysis of incident ADRD found no association with the genetic score (HR 1.02; 95% CI 0.81 to 1.28). Specific numerical details for the sensitivity analyses beyond the statement of consistency were not provided in the abstract.
These findings link a mechanism-anchored genetic proxy for higher systemic GLP1R expression to a lower risk of incident PDRD among adults with type 2 diabetes treated with GLP-1 receptor agonists. The results support the hypothesis that systemic GLP1R-mediated pathways may contribute to interindividual differences in observed PDRD risk in this patient population. The authors highlight that genetic instruments for GLP1R expression could inform hypotheses and design for future clinical trials targeting PDRD prevention or modification.
Limitations and additional details not reported in the abstract include the identities and dosing of specific GLP-1RAs used, granular adjustment covariates and balance diagnostics, absolute numbers of events, and the full results of each sensitivity analysis. The study design was observational and used a genetic proxy rather than direct measurement of systemic receptor expression; thus, while the genetic approach reduces some confounding, causal inference remains limited and should be evaluated alongside randomized controlled trial evidence.
Clinicians and researchers should interpret the association as hypothesis-generating evidence that systemic differences in GLP1R expression may modulate PDRD risk among GLP-1RA–treated patients with type 2 diabetes. Future work should report agent-specific effects, dose–response relationships, and replication in independent cohorts to inform trial design and mechanistic understanding.