title: Relation of genomic variants for Alzheimer disease dementia to common neuropathologies.
abstract: OBJECTIVE
  To investigate the associations of previously reported Alzheimer disease (AD) dementia genomic variants with common neuropathologies.
  
  
  METHODS
  This is a postmortem study including 1,017 autopsied participants from 2 clinicopathologic cohorts. Analyses focused on 22 genomic variants associated with AD dementia in large-scale case-control genome-wide association study (GWAS) meta-analyses. The neuropathologic traits of interest were a pathologic diagnosis of AD according to NIA-Reagan criteria, macroscopic and microscopic infarcts, Lewy bodies (LB), and hippocampal sclerosis. For each variant, multiple logistic regression was used to investigate its association with neuropathologic traits, adjusting for age, sex, and subpopulation structure. We also conducted power analyses to estimate the sample sizes required to detect genome-wide significance (p < 5 × 10(-8)) for pathologic AD for all variants.
  
  
  RESULTS
  APOE ε4 allele was associated with greater odds of pathologic AD (odds ratio [OR] 3.82, 95% confidence interval [CI] 2.67-5.46, p = 1.9 × 10(-13)), while ε2 allele was associated with lower odds of pathologic AD (OR 0.42, 95% CI 0.30-0.61, p = 3.1 × 10(-6)). Four additional genomic variants including rs6656401 (CR1), rs1476679 (ZCWPW1), rs35349669 (INPP5D), and rs17125944 (FERMT2) had p values less than 0.05. Remarkably, half of the previously reported AD dementia variants are not likely to be detected for association with pathologic AD with a sample size in excess of the largest GWAS meta-analyses of AD dementia.
  
  
  CONCLUSIONS
  Many recently discovered genomic variants for AD dementia are not associated with the pathology of AD. Some genomic variants for AD dementia appear to be associated with other common neuropathologies.
authors.affiliation: From the Department of Geriatrics (J.M.F.), University of Sao Paulo Medical School, Brazil; Department of Pathology (J.M.F., J.A.S.), Rush Alzheimer's Disease Center (J.M.F., L.Y., A.S.B., J.A.S., D.A.B.), and Department of Neurological Sciences (L.Y., A.S.B., J.A.S., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA. farfel@usp.br.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Farfel
authors.affiliation: From the Department of Geriatrics (J.M.F.), University of Sao Paulo Medical School, Brazil; Department of Pathology (J.M.F., J.A.S.), Rush Alzheimer's Disease Center (J.M.F., L.Y., A.S.B., J.A.S., D.A.B.), and Department of Neurological Sciences (L.Y., A.S.B., J.A.S., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.affiliation: From the Department of Geriatrics (J.M.F.), University of Sao Paulo Medical School, Brazil; Department of Pathology (J.M.F., J.A.S.), Rush Alzheimer's Disease Center (J.M.F., L.Y., A.S.B., J.A.S., D.A.B.), and Department of Neurological Sciences (L.Y., A.S.B., J.A.S., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Aron S
authors.initials: AS
authors.lastname: Buchman
authors.affiliation: From the Department of Geriatrics (J.M.F.), University of Sao Paulo Medical School, Brazil; Department of Pathology (J.M.F., J.A.S.), Rush Alzheimer's Disease Center (J.M.F., L.Y., A.S.B., J.A.S., D.A.B.), and Department of Neurological Sciences (L.Y., A.S.B., J.A.S., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; Harvard Medical School (P.L.D.), Boston; and Program in Medical and Population Genetics (P.L.D.), Broad Institute, Cambridge, MA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.affiliation: From the Department of Geriatrics (J.M.F.), University of Sao Paulo Medical School, Brazil; Department of Pathology (J.M.F., J.A.S.), Rush Alzheimer's Disease Center (J.M.F., L.Y., A.S.B., J.A.S., D.A.B.), and Department of Neurological Sciences (L.Y., A.S.B., J.A.S., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; 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 Department of Geriatrics (J.M.F.), University of Sao Paulo Medical School, Brazil; Department of Pathology (J.M.F., J.A.S.), Rush Alzheimer's Disease Center (J.M.F., L.Y., A.S.B., J.A.S., D.A.B.), and Department of Neurological Sciences (L.Y., A.S.B., J.A.S., D.A.B.), Rush University Medical Center, Chicago, IL; Program in Translational NeuroPsychiatric Genomics (P.L.D.), Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston; 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: D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics; D002544:Cerebral Infarction / Q000473:pathology*; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D016631:Lewy Bodies / Q000473:pathology*; D016015:Logistic Models; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000235:genetics; D017463:Receptors, Complement 3b / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C509991:CR1 protein, human; C477322:FERMT3 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D017463:Receptors, Complement 3b; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases