Objective: To evaluate the effect of genetic variants in β-glucocerebrosidase (GBA), apolipoprotein E (APOE), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) loci on the risk of developing dementia up to the first 10 years from diagnosis in a large population-based sample of patients with Parkinson’s disease (PD) from Northern Europe.

Background: Genetic variants have received increasing attention as modifiers of disease progression in PD and other neurodegenerative diseases. Common genetic variation of the GBA, APOE, MAPT, and SNCA loci have been linked to more rapid cognitive decline and dementia in PD (PDD), although studies have yielded mixed results.

Method: 1002 PD patients from the Parkinson’s Incidence Cohorts Collaboration (PICC), a project which has pooled data from six population-based, prospective cohorts (CamPaIGN, ICICLE-PD, NYPUM, ParkWest, PICNICS, and PINE), were genotyped for APOE ε2/ε3/ε4, MAPT H1/H2, and SNCA/rs356219 and screened for GBA mutations. Following in silico analysis, GBA mutations were classified as benign or severe. Patients were followed for up to ten years (median 6.5 years, max 10.5 years) and dementia assessed according to standardized criteria. We used Cox regression to evaluate the relationship between the variants and onset of PDD.

Results: During the follow-up, 287 patients (28.6%) progressed to dementia. The risk of PDD was associated with both APOE ε4 and GBA mutation carrier status, and, by the severity of the GBA mutation. Carriers of both GBA mutation and APOE ε4 progressed to PDD faster than carriers of risk genotype at GBA or APOE alone. There was no significant impact of MAPT H1/H1 haplotype or the SNCA rs356219 genotype.

Conclusion: GBA and APOE are significant determinants of PDD risk and have independent effects on the risk of progression to PDD in the general population of patients with PD. Inclusion of GBA and APOE genotyping could enhance the ability to predict the individual’s risk of dementia, which is of importance for the informed recruitment into clinical trials.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-factors-associated-with-dementia-in-parkinsons-disease-in-the-parkinsons-incidence-cohorts-collaboration-picc/