Who to Enroll in Parkinson Disease Prevention Trials? The Case for Genetically At-Risk Cohorts

Therapies that prevent the occurrence of Parkinson disease (PD) (primary prevention) or mitigate the progression of symptoms in those with early disease (secondary prevention) are a critical unmet need in disease management. Despite great promise, PD prevention trials have not yet demonstrated success. Initiation of treatment too late in the disease course and the heterogeneity of disease are obstacles that may have contributed to the failure. Genetically stratified groups offer many advantages to primary and secondary prevention trials. In addition to their ease of identification, they decrease disease heterogeneity on several levels. Particularly, they comprise a phenotypically and pathologically enriched group with defined clinical features, pathogenic mechanisms and associated proteins that may serve as specific trial endpoints, therapeutic targets and biomarkers for disease state, and pharmacodynamic and pharmacokinetic status. However, challenges arise from genetic variant heterogeneity, from reduced penetrance whereby many carriers will not develop PD, and in recruiting a population that will meet the desired outcome in the proposed study duration. In this review, we discussed the opportunities afforded by the enrollment of genetically stratified cohorts (i.e., leucine-rich repeat kinase 2 and glucocerebrosidase 1) into prevention trials with a primary focus on primary prevention trials. We also outlined challenges surrounding the enrollment of these cohorts and offered suggestions to leverage their many advantages.