APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease

Ignacio F. Mata, James B. Leverenz, Daniel Weintraub, John Q. Trojanowski, Howard I. Hurtig, Vivianna M. Van Deerlin, Beate Ritz, Rebecca Rausch, Shannon L. Rhodes, Stewart A. Factor, Cathy Wood-Siverio, Joseph Quinn, Kathryn (Kathy) Chung, Amie Peterson, Alberto J. Espay, Fredy J. Revilla, Johnna Devoto, Shu Ching Hu, Brenna A. Cholerton, Jia Y. WanThomas J. Montine, Karen L. Edwards, Cyrus P. Zabetian

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1405-1412
Number of pages8
JournalJAMA Neurology
Volume71
Issue number11
DOIs
StatePublished - Nov 1 2014

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Parkinson Disease
Verbal Learning
Trail Making Test
Semantics
Alleles
Genes
Cognition
Dementia
Sex Education
Executive Function
Cognitive Performance
Parkinson's Disease
Gene
Psychometrics
Haplotypes
Linear Models
Alzheimer Disease
Language
Genotype
Allele

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Clinical Neurology
  • Medicine(all)

Cite this

Mata, I. F., Leverenz, J. B., Weintraub, D., Trojanowski, J. Q., Hurtig, H. I., Van Deerlin, V. M., ... Zabetian, C. P. (2014). APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurology, 71(11), 1405-1412. https://doi.org/10.1001/jamaneurol.2014.1455

APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. / Mata, Ignacio F.; Leverenz, James B.; Weintraub, Daniel; Trojanowski, John Q.; Hurtig, Howard I.; Van Deerlin, Vivianna M.; Ritz, Beate; Rausch, Rebecca; Rhodes, Shannon L.; Factor, Stewart A.; Wood-Siverio, Cathy; Quinn, Joseph; Chung, Kathryn (Kathy); Peterson, Amie; Espay, Alberto J.; Revilla, Fredy J.; Devoto, Johnna; Hu, Shu Ching; Cholerton, Brenna A.; Wan, Jia Y.; Montine, Thomas J.; Edwards, Karen L.; Zabetian, Cyrus P.

In: JAMA Neurology, Vol. 71, No. 11, 01.11.2014, p. 1405-1412.

Research output: Contribution to journalArticle

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, J, Chung, KK, Peterson, A, Espay, AJ, Revilla, FJ, Devoto, J, Hu, SC, Cholerton, BA, Wan, JY, Montine, TJ, Edwards, KL & Zabetian, CP 2014, 'APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease', JAMA Neurology, vol. 71, no. 11, pp. 1405-1412. https://doi.org/10.1001/jamaneurol.2014.1455
Mata IF, Leverenz JB, Weintraub D, Trojanowski JQ, Hurtig HI, Van Deerlin VM et al. APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurology. 2014 Nov 1;71(11):1405-1412. https://doi.org/10.1001/jamaneurol.2014.1455
Mata, Ignacio F. ; Leverenz, James B. ; Weintraub, Daniel ; Trojanowski, John Q. ; Hurtig, Howard I. ; Van Deerlin, Vivianna M. ; Ritz, Beate ; Rausch, Rebecca ; Rhodes, Shannon L. ; Factor, Stewart A. ; Wood-Siverio, Cathy ; Quinn, Joseph ; Chung, Kathryn (Kathy) ; Peterson, Amie ; Espay, Alberto J. ; Revilla, Fredy J. ; Devoto, Johnna ; Hu, Shu Ching ; Cholerton, Brenna A. ; Wan, Jia Y. ; Montine, Thomas J. ; Edwards, Karen L. ; Zabetian, Cyrus P. / APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. In: JAMA Neurology. 2014 ; Vol. 71, No. 11. pp. 1405-1412.
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T1 - APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease

AU - Mata, Ignacio F.

AU - Leverenz, James B.

AU - Weintraub, Daniel

AU - Trojanowski, John Q.

AU - Hurtig, Howard I.

AU - Van Deerlin, Vivianna M.

AU - Ritz, Beate

AU - Rausch, Rebecca

AU - Rhodes, Shannon L.

AU - Factor, Stewart A.

AU - Wood-Siverio, Cathy

AU - Quinn, Joseph

AU - Chung, Kathryn (Kathy)

AU - Peterson, Amie

AU - Espay, Alberto J.

AU - Revilla, Fredy J.

AU - Devoto, Johnna

AU - Hu, Shu Ching

AU - Cholerton, Brenna A.

AU - Wan, Jia Y.

AU - Montine, Thomas J.

AU - Edwards, Karen L.

AU - Zabetian, Cyrus P.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - 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.

AB - 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.

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