Objective: To characterize the landscape of genotype-stratified clinical trials in Parkinson’s disease (PD) and atypical parkinsonian disorders (APD), including therapeutic targets, geographic representation, and trial design.

Background: PD is a clinically and biologically heterogeneous neurodegenerative disorder for which no disease-modifying therapy exists. Neurogenetic advances have identified pathways implicated in PD and APD, enabling precision medicine. Understanding the landscape of genotype-stratified clinical trials may help identify gaps and priorities for therapeutic development.

Method: A scoping review was conducted according to PRISMA-ScR guidelines. ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from inception to 15 February 2026. Two complementary strategies were used: phenotype-based searches including PD and related parkinsonian disorders (DLB, MSA, PSP, CBS) and genotype-based searches for 12 genes associated with PD and APD. Among 11,185 records screened, genotype-stratified trials (i.e.those recruiting genetic variant carriers) were included. Data on therapeutic intervention, trial design, recruitment status, study site location, clinical and biological outcomes were extracted and analysed.

Results: 59 genotype-stratified trials were identified across 7 genetic targets. Most focused on GBA1 (n=23), followed by C9orf72 (n=13),GRN (n=11),LRRK2 (n=9),MAPT (n=4),PINK1 (n=2),PRKN (n=2), with 5 trials recruiting variants in two genes (Fig.1). None were identified for SNCA, PARK7, VPS35, Rab32 or DCTN1 carriers. Study sites were concentrated in North America and Western Europe (87.8%,n=559); 97.5% (n=621) were in high-income countries, with minimal representation from upper-middle-income countries (2.5%,n=16) and none in lower-middle- or low-income countries (Fig.2). Most trials (71.2%,n=42) incorporated biomarker endpoints. Only 8.5% (n=5) and 1.7% (n=1) were phase 3 and phase 4 trials with disease rating scales as primary endpoints. 14 trials reported outcomes in 11 publications, including 8 positive phase 1 and 1 positive phase 2 study. 10 trials were terminated prematurely and one withdrawn.

Conclusion: Genotype-stratified trials in PD and APD face major challenges, including translational delays and geographic disparities. Addressing these gaps is essential to advance genomics-guided therapies in parkinsonian disorders.

Figure 1

Figure 2

References: [1] Su D, Cui Y, He C et al. Projections for prevalence of Parkinson’s disease and its driving factors in 195 countries and territories to 2050: modelling study of Global Burden of Disease Study 2021. BMJ. 2025 Mar 5;388:e080952. doi: 10.1136/bmj-2024-080952. PMID: 40044233; PMCID: PMC11881235.

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