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APOE, MAPT, SNCA, and Cognitive Performance in Parkinson Disease

Importance
Cognitive impairment (CI) is a common and disabling problem in Parkinson’s disease (PD) that is not well understood and is difficult to treat. Identification of genetic variants that influence the rate of cognitive decline or pattern of early cognitive deficits in PD might provide a clearer understanding of the etiopathogenesis of this important non-motor feature.

Objectives
To determine if common variation in the APOE, MAPT, and SNCA genes is associated with cognitive performance in patients with PD.

Design, Setting and Participants
We studied 1,079 PD patients from six academic centers in the U.S. who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention/executive function (Letter-Number Sequencing and Trail Making Test), language processing (semantic and phonemic verbal fluency), visuospatial skills (Benton Judgment of Line Orientation) and global cognitive function (Montreal Cognitive Assessment [MoCA]). Subjects were genotyped for APOE ε2/ε3/ε4, MAPT H1/H2 haplotypes, and SNCA rs356219. Linear regression was used to test for association between genotype and baseline cognitive performance adjusting for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the nine comparisons that were performed for each gene.

Main Outcomes and Measures
Nine variables derived from seven psychometric tests.

Results
APOE ε4 was associated with lower performance on HVLT-R total learning (P=6.7×10−6; corrected P [Pc]=6.0×10−5), delayed recall (P=0.001; Pc=0.009), and recognition discrimination index (P=0.004; Pc=0.04), and semantic verbal fluency (P=0.002; Pc=0.018), Letter-Number sequencing (P=1 × 10−5; Pc=9 × 10−5), and Trails B-A (P=0.002; Pc=0.018). In a subset of 645 non-demented patients, APOE ε4 was associated with lower scores on HVLT-R total learning (P=0.005; Pc=0.045) and semantic verbal fluency (P=0.005; Pc=0.045). MAPT and SNCA variants were not associated with scores on any tests.

Conclusions and Relevance
Our data indicate that APOE ε4 is an important predictor of cognitive function in PD across multiple domains. Among non-demented PD patients, APOE ε4 was only associated with lower performance on word list learning and semantic verbal fluency, a pattern more typical of the cognitive deficits seen in early Alzheimer’s disease than PD.

Citation

"APOE, MAPT, SNCA, and Cognitive Performance in Parkinson Disease" JAMA Neurology (2014): 1,405–12