title: Genetic susceptibility for Alzheimer disease neuritic plaque pathology.
abstract: OBJECTIVE
  While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques.
  
  
  OBJECTIVE
  To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait.
  
  
  METHODS
  Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers.
  
  
  METHODS
  A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir.
  
  
  RESULTS
  Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition.
  
  
  CONCLUSIONS
  These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.
authors.affiliation: Departments of Neurology and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas2Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Keenan
authors.forename: Lori B
authors.initials: LB
authors.lastname: Chibnik
authors.forename: Adam
authors.initials: A
authors.lastname: Fleisher
authors.forename: Pradeep
authors.initials: P
authors.lastname: Thiyyagura
authors.forename: Auttawut
authors.initials: A
authors.lastname: Roontiva
authors.forename: Cristin
authors.initials: C
authors.lastname: McCabe
authors.forename: Nikolaos A
authors.initials: NA
authors.lastname: Patsopoulos
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: Lei
authors.initials: L
authors.lastname: Yu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Denis A
authors.initials: DA
authors.lastname: Evans
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001931:Brain Mapping; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies