title: Effect of complement CR1 on brain amyloid burden during aging and its modification by APOE genotype.
abstract: BACKGROUND
  The rs3818361 single nucleotide polymorphism in complement component (3b/4b) receptor-1 (CR1) is associated with increased risk of Alzheimer's disease (AD). Although this novel variant is associated with a small effect size and is unlikely to be useful as a predictor of AD risk, it might provide insights into AD pathogenesis. We examined the association between rs3818361 and brain amyloid deposition in nondemented older individuals.
  
  
  METHODS
  We used (11)C-Pittsburgh Compound-B positron emission tomography to quantify brain amyloid burden in 57 nondemented older individuals (mean age 78.5 years) in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging. In a replication study, we analyzed (11)C-Pittsburgh Compound-B positron emission tomography data from 22 cognitively normal older individuals (mean age 77.1 years) in the Alzheimer's Disease Neuroimaging Initiative dataset.
  
  
  RESULTS
  Risk allele carriers of rs3818361 have lower brain amyloid burden relative to noncarriers. There is a strikingly greater variability in brain amyloid deposition in the noncarrier group relative to risk carriers, an effect explained partly by APOE genotype. In noncarriers of the CR1 risk allele, APOE ε4 individuals showed significantly higher brain amyloid burden relative to APOE ε4 noncarriers. We also independently replicate our observation of lower brain amyloid burden in risk allele carriers of rs3818361 in the Alzheimer's Disease Neuroimaging Initiative sample.
  
  
  CONCLUSIONS
  Our findings suggest complex mechanisms underlying the interaction of CR1, APOE, and brain amyloid pathways in AD. Our results are relevant to treatments targeting brain Aβ in nondemented individuals at risk for AD and suggest that clinical outcomes of such treatments might be influenced by complex gene-gene interactions.
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. thambisettym@mail.nih.gov
authors.forename: Madhav
authors.initials: M
authors.lastname: Thambisetty
authors.forename: Yang
authors.initials: Y
authors.lastname: An
authors.forename: Michael
authors.initials: M
authors.lastname: Nalls
authors.forename: Jitka
authors.initials: J
authors.lastname: Sojkova
authors.forename: Shanker
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhou
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.forename: Susan M
authors.initials: SM
authors.lastname: Resnick
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D000682:Amyloid / Q000235:genetics* / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009483:Neuropsychological Tests; D011877:Radionuclide Imaging; D017463:Receptors, Complement 3b / Q000235:genetics* / Q000378:metabolism
chemical_list: D000682:Amyloid; D001057:Apolipoproteins E; D017463:Receptors, Complement 3b