Genome-wide Prediction of Dementia in Parkinson's Disease Progression, not susceptibility, is the major determinant of patients' well-being. Dementia is one of the most debilitating manifestations of disease progression in patients with Parkinson's. It negatively impacts quality of life, burdens caregivers and increases health costs. Existing therapies cannot prevent the decline from initial motor symptoms to cognitive impairment. The pace of deterioration varies dramatically between patients for reasons that are poorly understood. Limited evidence has been found for a proposed association between prognosis and susceptibility variants. Our initial studies provide compelling evidence for distinct genome loci predictive of memory loss. We hypothesize that novel prognosis loci will powerfully predict a patient's risk for developing Parkinson's disease dementia. Previous genome-wide association studies were time-static, cross-sectional, case-control studies that cannot address the time dimension critical for understanding progression. To systematically decode the genetic architecture of cognitive progression in Parkinson's, here we will perform an unbiased, longitudinal genome-wide survival study with deep imputation of nineteen cohorts from North America and Europe. More than six thousand patients with Parkinson?s disease and over fifty thousand cognitive assessments will be analyzed using Cox proportional hazards and mixed random and fixed effect models.
In Aim 1, we will discover novel loci associated with progression to Parkinson's disease dementia.
In Aim 2, we will replicate and verify forwarded genetic variants in an independent population.
In Aim 3, we will build and test a versatile Polygenic Hazard Score to accurately forecast risk of future cognitive decline. This study is poised to elucidate progression loci for Parkinson?s disease dementia, improve clinical prognostication, and transform clinical trial design. The genetic drivers will point to a distinct biology of cognitive decline that could inspire new therapeutic directions.
For most neurological disorders the main driver of patients' well-being is disease progression, not susceptibility. The reasons for divergent disease progression between patients are poorly understood. The pace of progression varies considerably, ranging from a manageable functional decline to an accelerated course that leaves patients rapidly with dementia. This study will develop a robust polygenic hazard score associated with risk of progression to Parkinson's disease dementia. It will elucidate the genetic architecture of cognitive decline in PD and inspire new therapeutic directions. More generally, these data will contribute towards a precision medicine poised to transform healthcare.
