Background Cognitive decline is a debilitating manifestation of disease progression in Parkinson’s disease. We aimed to develop a clinical-genetic predictors to forecast disease progression in patients with the disease. Study Design and Specific Aims. In Specific Aim 1, we are developing genome-wide polygenic scores and clincal-genetic predictors in thousands of patients followed for up to 12 years with tens of thousands of longitudinal visits in the IGPP Consortium (PI Scherzer). We use Cox models, LMM, and recently developed computational algorithms to derive and evaluate robust predictors of disease progression. In Specific Aim 2, we will replicate the clinical and genetic predictors in the UK Biobank cohort and evaluate their predictive performance for early time points. With these predictors we will identify a subset of the patient population at risk for rapid progression and others that enjoy considerable resilience. Impact. Predictors of progression risk will augment prognostication and clinical trial design. They will enrich trials with patients who have a more aggressive disease course and are therefore likely to show the greatest benefits from interventions. They will elucidate new genetic driver pathways and advance precision medicine.
