Abstract
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.
Highlights
Recent genome-wide association studies (GWAS) have reported an overlap between Parkinson disease (PD) and the most common forms of dementia including Alzheimer disease (AD), dementia with Lewy bodies (DLB) and Frontotemporal dementia (FTD) (Guerreiro et al, 2015; Ferrari et al, 2017)
Multiple variants associated with PD risk have been identified as risk factors for AD, DLB, or FTD including variants in the following genes: Triggering receptor expressed on myeloid cells 2 (TREM2), Microtubule-associated protein tau (MAPT), C9orf72, Glucocerebrosidase (GBA), and Apolipoprotein E (APOE) (Parsian et al, 2002; Harms et al, 2013; Davis et al, 2015; Benitez et al, 2016)
220 pathogenic mutations in the PSEN1 gene have been reported in AD patients worldwide, whereas 27 and 16 pathogenic mutations have been described in the Amyloid protein precursor (APP) and PSEN2 genes, respectively (Cruts et al, 2012)
Summary
Recent genome-wide association studies (GWAS) have reported an overlap between Parkinson disease (PD) and the most common forms of dementia including Alzheimer disease (AD), dementia with Lewy bodies (DLB) and Frontotemporal dementia (FTD) (Guerreiro et al, 2015; Ferrari et al, 2017). We recently reported the presence of leucinerich repeat kinase 2 (LRRK2), p.G2019S mutation in members of two multigenerational families with AD and a suggestive association of variants in the PTEN-induced putative kinase 1 (PINK1) gene with AD (Fernández et al, 2017). These results suggest a genetic overlap between familial AD and PD. The contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established
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