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

Area of Science:

• Neuroscience and Genetics
• Clinical Trial Design
• Parkinson Disease Research

Background:

• Parkinson disease (PD) prevention strategies are a significant unmet need.
• Previous PD prevention trials have faced challenges due to late treatment initiation and disease heterogeneity.
• Genetically stratified cohorts present a promising avenue for improving PD prevention trial success.

Purpose of the Study:

• To review the opportunities and challenges of using genetically stratified cohorts in Parkinson disease prevention trials.
• To focus on the potential of leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase 1 (GBA1) cohorts for primary prevention.

Main Methods:

• Review of existing literature on Parkinson disease genetics and prevention trials.
• Analysis of the advantages of genetically stratified cohorts, including reduced heterogeneity and defined biomarkers.
• Discussion of challenges such as genetic variant heterogeneity and reduced penetrance.

Main Results:

• Genetically stratified cohorts offer a phenotypically and pathologically enriched population for trials.
• These cohorts provide defined clinical features, pathogenic mechanisms, and potential biomarkers.
• Challenges include genetic variant diversity and recruiting sufficient participants for desired outcomes.

Conclusions:

• Genetically stratified cohorts, particularly LRRK2 and GBA1, hold significant potential for Parkinson disease primary prevention trials.
• Overcoming enrollment and genetic heterogeneity challenges is crucial for leveraging the advantages of these cohorts.
• Strategic approaches are needed to maximize the benefits of genetically stratified populations in PD prevention research.