title: TOMM40'523 variant and cognitive decline in older persons withAPOEε3/3 genotype.
abstract: OBJECTIVE
  To interrogate a poly-T variant (rs10524523, '523) inTOMM40, a gene adjacent to theAPOEgene on chromosome 19, in older persons withAPOEε3/3 homozygosity for association with cognitive decline, the clinical hallmark of Alzheimer disease (AD).
  
  
  METHODS
  Data came from participants in 2 cohort studies of aging and dementia who underwent annual clinical evaluations for up to 21 years.APOEandTOMM40'523 genotypes were determined from DNA from blood or brain samples. Linear mixed models compared the rates of decline in cognition amongAPOEε3/3 carriers with different '523 genotypes.
  
  
  RESULTS
  The 1,170APOEε3/3 homozygotes were of European ancestry, were free of dementia at baseline, and had an average age of 78.5 years at baseline. Three major genotypes at the '523 variant were linked toAPOEε3/3; 26.5% had 2 short poly-Ts (S/S), 48.5% had 1 short and 1 very long poly-T (S/VL), and 24.0% had 2 very long poly-Ts (VL/VL). Participants with '523-S/S had faster decline in global cognition than participants with '523-S/VL or VL/VL (p= 0.002). The same association was observed for episodic memory (p< 0.001) and semantic memory (p= 0.003) but not for working memory, perceptual speed, or visuospatial ability.
  
  
  CONCLUSIONS
  Our data reveal an association ofAPOEε3/3-TOMM40'523 haplotypes with cognitive decline in community-based older persons such that the S/S poly-T genotype is related to faster cognitive decline, primarily in the domains of episodic and semantic memory.
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA. lei_yu@Rush.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wilson
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Burns
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Saunders
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Chris
authors.initials: C
authors.lastname: Gaiteri
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Barnes
authors.affiliation: From the Rush Alzheimer's Disease Center (L.Y., R.S.W., C.G., L.L.B., D.A.B.) and Department of Neurological Sciences (L.Y., R.S.W., C.G., L.L.B., D.A.B.), Rush University Medical Center, Chicago, IL; Department of Neurology (M.W.L., A.D.R., A.M.S.), Duke University School of Medicine, Durham; Zinfandel Pharmaceuticals, Inc (D.K.B., A.D.R.), Research Triangle Park, NC; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
mesh_terms: D000368:Aged; D053318:Apolipoprotein E3 / Q000235:genetics*; D003071:Cognition; D060825:Cognitive Dysfunction / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D060005:Genotyping Techniques; D006720:Homozygote; D006801:Humans; D016014:Linear Models; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008609:Mental Status Schedule; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009483:Neuropsychological Tests; D014481:United States; D044465:White People / Q000235:genetics
chemical_list: D053318:Apolipoprotein E3; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human