Preparing for Parkinson's disease prevention trials: Current progress and future directions.

In recent decades, numerous clinical trials have aimed to delay or prevent Parkinson's disease (PD) progression. Despite the theoretical promise and encouraging preclinical data, none have shown clear efficacy in slowing or preventing PD progression, related to several key limitations. Conventional motor and non-motor scales often fall short in detecting early disease changes, while the heterogeneity of PD phenotypes complicates treatment efficacy. The timing of interventions is also critical, as most trials target patients already in advanced stages of neurodegeneration. A deeper understanding of the preclinical phase and the emergence of new pathological frameworks have shifted the focus toward preventing the onset of clinical PD. Recent advances in biomarker research, including tissue, fluid, and imaging markers, are poised to transform PD research by improving patient selection, stratification, and disease progression monitoring. New biologically grounded frameworks for classifying synucleinopathies aim to distinguish biological subtypes from clinical phenotypes, enabling more targeted prevention trials. Successful PD prevention trials will require early enrollment of individuals at the highest risk, employing low-risk personalized interventions, with biomarkers or sensitive clinical markers as endpoints. Early involvement of key stakeholders will be essential to ensure that trials are timely, ethically sound, and aligned with the needs of the PD community.