Genome-wide Polygenic Score to Predict Progression from Parkinson´s Disease to Dementia

Parkinson’s disease dementia (PDD) is one of the most debilitating symptoms of disease progression in Parkinson’s disease (PD), affecting nearly all PD patients at advanced disease stages. Nonetheless, treatments that can effectively prevent or modify cognitive decline in PD are not available.

Due to the heterogeneity of trial populations and experimental drugs lacking mechanistic support, current trials designed for PDD therapies also tend to fail.

Our project thus proposes to 1) develop genome-wide polygenic scores (GPSs) predictive of cognitive decline in PD as a patient stratification tool, 2) validate the derived GPSs and test their predictive performance, and 3) translate the GPSs into PDD mechanism and evaluate the observational effect of mechanistically implicated PDD drugs.

The project will be a 3-year collaboration between the US and Sweden, starting in July 2022.

For aims 1&2, we will perform rigorous survival and longitudinal analyses of genotyping and clinical data collected from 18 longitudinal cohorts of 7,161 PD patients with 43,434 study visits.

For aim 3, we will explore PDD mechanism via bioinformatic analysis of genetic data covered by the GPS and estimate the association of genetically supported dementia drugs with PDD risk in a Swedish register-based cohort design.

Our research outcome will immediately benefit future trials for PDD treatments and further promote a shift towards patient-centred, mechanism-directed precision medicine for PD.