Although studies have generated conflicting findings, common genetic variation in apolipoprotein E (APOE), β-glucocerebrosidase (GBA), microtubule-associated protein tau (MAPT), and α-synuclein (SNCA) has been related to cognitive impairment in Parkinson’s disease (PD). To assess the impact of APOE, GBA, MAPT, and SNCA genetic variations on cognitive decline and dementia risk in a pooled study of six longitudinal, non-selective, population-based cohorts of newly diagnosed Parkinson’s disease patients.
About 1,002 Parkinson’s disease patients were genotyped for at least one of the following genes: APOE-ε4, GBA mutations, MAPT H1/H2, or SNCA rs356219. Researchers used linear mixed models to examine the effect of genotype on the rate of cognitive decline (Mini-Mental State Examination, MMSE) and Cox regression to examine the development of dementia (diagnosed using standardized criteria); multiple comparisons were accounted for using Benjamini-Hochberg corrections.
Carriers of APOE-ε4 (n=281, 29.7%) and GBA mutations (n=100, 10.3%) exhibited quicker cognitive decline and were at higher risk of dementia development (APOE-ε4, HR 3.57, P < 0.001; GBA mutations, HR 1.76, P = 0.001) than non-carriers. Carriers of both risk genotypes (n=23) had a higher risk of cognitive decline and dementia (HR 5.19, P < 0.001). There were no significant impacts for MAPT or SNCA rs356219. GBA and APOE-ε4 genotyping have the potential to enhance the prediction of cognitive decline in Parkinson’s disease, which is crucial for clinical trial selection and perhaps tailored therapy.