Alzheimer disease associated variants in SORL1 accelerate dementia development in Parkinson disease

Abstract Objective Dementia in Parkinson disease (PD) is a common occurrence, and shows a marked overlap at a clinical and pathological level with Alzheimer’s disease (AD), suggesting they share underlying disease mechanisms. Genetic variants in SORL1 have been identified in patients with AD, but a possible role in other dementias is unknown. The aim of this study was to investigate whether common polymorphisms in SORL1 affect the risk of developing dementia in a population-based cohort of patients with incident PD. Methods One common, nonsynonymous SORL1 variant (rs2298813; A528T) was identified in whole exome sequencing data from 185 patients with PD from the Norwegian ParkWest study, who had been followed up to the 7-year visit after diagnosis. A528T was tested for association with PD risk, the development of dementia, and in a subset of patients (n = 103) for associations with established AD cerebrospinal fluid (CSF) biomarkers measured at the time of PD diagnosis. Results We found an association of A528T carrier status with increased risk of developing PD dementia (HR 2.31; 95% CI 1.09–4.90; p = 0.03) compared to non-carriers. Additionally, A528T carrier status was associated with a reduced ratio of CSF β-amyloid 42 to p-Tau (p = 0.014) but no alterations in absolute AD marker levels (all p > 0.05) at the time of PD diagnosis. Conclusion Our results show the first association of the AD risk factor SORL1 with incident dementia in PD, providing new evidence that AD related disease mechanisms may contribute to dementia in a subset of patients with PD. Finding support for a shared etiology for AD and PD dementia provides new directions for research into treatments for these diseases.