title: APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington3Department of Neurology, University of Washington School of Medicine, Seattle.
authors.forename: Ignacio F
authors.initials: IF
authors.lastname: Mata
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington3Dep.
authors.forename: James B
authors.initials: JB
authors.lastname: Leverenz
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia7Department of Psychiatry, University of Pennsylvania, Philadelphia8Parkinson's Disease Research, Education, and Clinical Center and Mental Illness Research, Education, and Clinical Center.
authors.forename: Daniel
authors.initials: D
authors.lastname: Weintraub
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia10Institute on Aging, University of Pennsylvania, Philadelphia.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia.
authors.forename: Howard I
authors.initials: HI
authors.lastname: Hurtig
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Vivianna M
authors.initials: VM
authors.lastname: Van Deerlin
authors.affiliation: Department of Epidemiology, School of Public Health, University of California, Los Angeles12Department of Environmental Health Sciences, School of Public Health, University of California, Los Angeles13Department of Neurology, University of California, Los.
authors.forename: Beate
authors.initials: B
authors.lastname: Ritz
authors.affiliation: Department of Neurology, University of California, Los Angeles.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rausch
authors.affiliation: Department of Epidemiology, School of Public Health, University of California, Los Angeles.
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Rhodes
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Factor
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Cathy
authors.initials: C
authors.lastname: Wood-Siverio
authors.affiliation: Parkinson's Disease Research, Education, and Clinical Center,Portland Veterans Affairs Medical Center, Portland, Oregon16Department of Neurology, Oregon Health and Science University, Portland.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Quinn
authors.affiliation: Parkinson's Disease Research, Education, and Clinical Center,Portland Veterans Affairs Medical Center, Portland, Oregon16Department of Neurology, Oregon Health and Science University, Portland.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Chung
authors.affiliation: Parkinson's Disease Research, Education, and Clinical Center,Portland Veterans Affairs Medical Center, Portland, Oregon16Department of Neurology, Oregon Health and Science University, Portland.
authors.forename: Amie L
authors.initials: AL
authors.lastname: Peterson
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Espay
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio18Department of Neurology, Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio.
authors.forename: Fredy J
authors.initials: FJ
authors.lastname: Revilla
authors.affiliation: Department of Neurology and Rehabilitation Medicine, University of Cincinnati, Cincinnati, Ohio.
authors.forename: Johnna
authors.initials: J
authors.lastname: Devoto
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington3Dep.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hu
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington4Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.
authors.forename: Brenna A
authors.initials: BA
authors.lastname: Cholerton
authors.affiliation: Department of Epidemiology, University of Washington, Seattle20currently with Department of Epidemiology, University of California, Irvine.
authors.forename: Jia Y
authors.initials: JY
authors.lastname: Wan
authors.affiliation: Department of Pathology, University of Washington School of Medicine, Seattle.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.affiliation: Department of Epidemiology, University of Washington, Seattle20currently with Department of Epidemiology, University of California, Irvine.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Edwards
authors.affiliation: Geriatric Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington2Parkinson's Disease Research, Education, and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington3Dep.
authors.forename: Cyrus P
authors.initials: CP
authors.lastname: Zabetian
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics; D053327:Apolipoprotein E4 / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D003072:Cognition Disorders / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008568:Memory / Q000502:physiology; D008875:Middle Aged; D009483:Neuropsychological Tests; D010300:Parkinson Disease / Q000235:genetics*; D051844:alpha-Synuclein / Q000235:genetics*; D016875:tau Proteins / Q000235:genetics*
chemical_list: D053327:Apolipoprotein E4; C054369:MAPT protein, human; C497604:SNCA protein, human; D051844:alpha-Synuclein; D016875:tau Proteins