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

JAMA Neurol. 2014 Sep 1. doi: 10.1001/jamaneurol.2014.1455. [Epub ahead of print]

Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Hurtig HI, Van Deerlin VM, Ritz B, Rausch R, Rhodes SL, Factor SA, Wood-Siverio C, Quinn JF, Chung KA, Peterson AL, Espay AJ, Revilla FJ, Devoto J, Hu SC, Cholerton BA, Wan JY, Montine TJ, Edwards KL, Zabetian CP.

IMPORTANCE:

Cognitive impairment is a common and disabling problem in Parkinson 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 nonmotor feature.

OBJECTIVE:

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

DESIGN, SETTING, AND PARTICIPANTS:

We studied 1079 PD patients from 6 academic centers in the United States who underwent assessments of memory (Hopkins Verbal Learning Test-Revised [HVLT-R]), attention and executive function (Letter-Number Sequencing Test and Trail Making Test), language processing (semantic and phonemic verbal fluency tests), visuospatial skills (Benton Judgment of Line Orientation test), and global cognitive function (Montreal Cognitive Assessment). Participants underwent genotyping for the APOE ε2/ε3/ε4 alleles, MAPT H1/H2 haplotypes, and SNCA rs356219. We used linear regression to test for association between genotype and baseline cognitive performance with adjustment for age, sex, years of education, disease duration, and site. We used a Bonferroni correction to adjust for the 9 comparisons that were performed for each gene.

MAIN OUTCOMES AND MEASURES:

Nine variables derived from 7 psychometric tests.

RESULTS:

The APOE ε4 allele was associated with lower performance on the HVLT-R Total Recall (P = 6.7 × 10-6; corrected P [Pc] = 6.0 × 10-5), Delayed Recall (P = .001; Pc = .009), and Recognition Discrimination Index (P = .004; Pc = .04); a semantic verbal fluency test (P = .002; Pc = .02); the Letter-Number Sequencing Test (P = 1 × 10-5; Pc = 9 × 10-5); and Trail Making Test B minus Trail Making Test A (P = .002; Pc = .02). In a subset of 645 patients without dementia, the APOE ε4 allele was associated with lower scores on the HVLT-R Total Recall (P = .005; Pc = .045) and the semantic verbal fluency (P = .005; Pc = .045) measures. Variants of MAPT and SNCA were not associated with scores on any tests.

CONCLUSIONS AND RELEVANCE:

Our data indicate that the APOE ε4 allele is an important predictor of cognitive function in PD across multiple domains. Among PD patients without dementia, the APOE ε4 allele 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 disease than PD.