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Background:  The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established.   Objective:  To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients.   Methods:  We analyzed the coding regions of the amyloid-beta precursor protein ( APP ), Presenilin 1 and 2 ( PSEN1, PSEN2 ), and Granulin ( GRN ) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and  APOE  carrier status.   Results:  Known AD pathogenic mutations in the  PSEN1  (p.A79V) and  PSEN2  (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the  GRN  and  PSEN1  genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the  APP, PSEN1, PSEN2 , and  GRN  genes exhibit lower cognitive tests scores than non-carrier PD patients ( p  = 2.0 × 10 −4 ), independent of age at PD diagnosis, age at evaluation,  APOE  status or recruitment site.   Conclusions:  Pathogenic mutations in the Alzheimer disease-causing genes ( PSEN1  and  PSEN2)  are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.

Pleiotropic Effects of Variants in Dementia Genes in Parkinson Disease