title: Exploring candidate gene associations with neuropsychological performance.
abstract: We hypothesize that quantitative phenotypes related to Alzheimer's disease (AD), rather than the dichotomous disease phenotype, will increase the statistical power for identifying genetic risk factors. Neuropsychological test scores, which allow for the measurement of loss of cognitive function over time, are a particularly promising option for this approach. Using data from a cohort study of prodromal AD in 365 community-recruited subjects with and without memory problems with a baseline and often one or more follow-up administrations of a detailed neuropsychological test battery, we performed both cross-sectional and longitudinal analyses using the known AD gene APOE and four other putative AD genes as predictors. APOE and a promoter polymorphism in insulin degrading enzyme (IDE_4U) showed evidence for association with cross-sectional and longitudinal changes in memory (P = 0.016-0.025) and other cognitive functions. APOE and a polymorphism in the alpha-2-macroglobulin gene (A2M18i) also showed evidence for association with cross-sectional and longitudinal changes in executive functioning (P = 0.010-0.042). In some cases, longitudinal analysis offered stronger evidence for association than could be seen cross-sectionally. These preliminary results suggest that this approach has promised the development of a quantitative phenotype related to AD, but more elaborate methods will be required to address multiple comparisons issues in the setting of correlated data.
authors.affiliation: Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, Colorado 80309-0447, USA. matthew.mcqueen@colorado.edu
authors.forename: Matthew B
authors.initials: MB
authors.lastname: McQueen
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.forename: Christoph
authors.initials: C
authors.lastname: Lange
authors.forename: K D
authors.initials: KD
authors.lastname: Becker
authors.forename: Marilyn S
authors.initials: MS
authors.lastname: Albert
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Deborah
authors.initials: D
authors.lastname: Blacker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics*; D053329:Apolipoprotein E2 / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D003072:Cognition Disorders / Q000175:diagnosis / Q000235:genetics; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008568:Memory / Q000502:physiology*; D008875:Middle Aged; D009483:Neuropsychological Tests; D018570:Risk Assessment; D013647:Task Performance and Analysis; D000511:alpha-Macroglobulins / Q000235:genetics*
chemical_list: D053329:Apolipoprotein E2; D053327:Apolipoprotein E4; D000511:alpha-Macroglobulins