Polygenic Score for Dementia in Parkinson's Disease

Dementia is one of the most challenging and debilitating outcomes for individuals living with Parkinson’s disease (PD), affecting not only patients but also their families and the broader healthcare system. While PD is widely recognized as a complex disorder with considerable variability in disease progression, the reasons some patients rapidly develop dementia while others remain cognitively resilient are poorly understood. This research project seeks to address this gap by investigating whether genome-wide polygenic scores—quantitative measures that integrate information from thousands of common genetic variants—can predict an individual’s risk of progressing from PD to dementia. The central research questions focus on whether such scores can reliably forecast dementia onset, identify patients at higher risk for rapid progression, and improve early prognostication. To achieve these aims, the research team will analyze genetic data from thousands of PD patients tracked over up to twelve years and tens of thousands of clinical visits. Using advanced computational algorithms, the investigators will develop polygenic scores that distill subtle genetic signals into a single, actionable metric. These scores will then be rigorously tested in five independent longitudinal cohorts to evaluate their predictive performance, especially at early stages of PD. By identifying genetic patterns associated with both vulnerability and resilience to dementia, the study aims to clarify the biological mechanisms underlying disease heterogeneity. The significance of this work extends to clinical trial design, as the polygenic score could enable more precise patient stratification—enriching trials with participants who are most likely to benefit from interventions targeting cognitive decline. Furthermore, the research aligns with strategic priorities in neurological disease research, particularly those emphasizing cognition and precision medicine in PD. In the longer term, the project’s outcomes could inform risk assessment for civilians and Veterans diagnosed with PD, facilitating earlier interventions and tailored care strategies. By integrating genetic insights into clinical practice, this study has the potential to advance precision medicine, improve quality of life for PD patients, and reduce the societal burden of dementia. Through collaboration with multiple longitudinal cohorts and leveraging state-of-the-art data analytics, the project directly addresses the Neuro Exposure Treatment Parkinson’s (NETP) Program’s goals to understand the mechanisms of cognitive symptoms and disease heterogeneity in PD, setting the stage for future breakthroughs in diagnosis, prognosis, and therapeutic development.