Association of PICALM with Cognitive Impairment in Parkinson's Disease.

Abstract

Cognitive impairment is one of the most disabling nonmotor symptoms in Parkinson's disease (PD). Recently, a genome-wide association study in Alzheimer's disease has identified the PICALM rs3851179 polymorphism as one of the most significant susceptibility genes for Alzheimer's disease after APOE. The aim of this study was to determine the potential role of PICALM and its genetic interaction with APOE in the development of cognitive decline in PD. A discovery cohort of 712 patients with PD were genotyped for PICALM (rs3851179) and APOE (rs429358 and rs7412) polymorphisms. The association of PICALM and APOE-PICALM genetic interaction with cognitive dysfunction in PD was studied using logistic regression models, and the relationship of PICALM with cognitive decline onset was assessed with Cox regression analysis. PICALM effect was then replicated in an international, independent cohort (Parkinson's Progression Markers Initiative, N = 231). PICALM rs3851179 TT genotype was significantly associated with a decreased risk of cognitive impairment in PD (TT vs. CC + CT, P = 0.041, odds ratio = 0.309). Replication studies further demonstrated its protective effect on cognitive impairment in PD. In addition, the protective effect of the PICALM rs3851179 TT genotype was more pronounced in the APOE ε4 (-) carriers from the discovery cohort (P = 0.037, odds ratio = 0.241), although these results were not replicated in the Parkinson's Progression Markers Initiative cohort. Our results support the fact that PICALM is associated with cognitive impairment in PD. The understanding of its contribution to cognitive decline in PD could provide new targets for the development of novel therapies. © 2020 International Parkinson and Movement Disorder Society.