title: Autosomal recessive causes likely in early-onset Alzheimer disease.
abstract: OBJECTIVE
  To determine the genetic contribution to non-autosomal dominant early-onset Alzheimer disease (EOAD) (onset age ≤60 years) cases and identify the likely mechanism of inheritance in those cases.
  
  
  METHODS
  A liability threshold model of disease was used to estimate heritability of EOAD and late-onset Alzheimer disease (AD) using concordance for AD among parent-offspring pairs.
  
  
  METHODS
  The Uniform Data Set, whose participants were collected from 32 US Alzheimer's Disease Centers, maintained by the National Alzheimer's Coordinating Center.
  
  
  METHODS
  Individuals with probable AD and detailed parental history (n = 5370).
  
  
  METHODS
  The concordance among relatives and heritability of EOAD and late-onset AD.
  
  
  RESULTS
  For late-onset AD (n = 4302), we found sex-specific parent-offspring concordance that ranged from approximately 10% to 30%, resulting in a heritability of 69.8% (95% confidence interval, 64.6%-75.0%), and equal heritability for both sexes regardless of parental sex. For EOAD (n = 702), we found that the parent-offspring concordance was 10% or less and concordance among siblings was 21.6%. Early-onset AD heritability was 92% to 100% for all likely values of EOAD prevalence.
  
  
  CONCLUSIONS
  We confirm late-onset AD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the patterns of observed concordance for parent-offspring pairs and among siblings lead us to reject the hypotheses that EOAD is a purely dominant, mitochondrial, X-linked, or polygenic disorder. The most likely explanation of the data is that approximately 90% of EOAD cases are due to autosomal recessive causes.
authors.affiliation: Veterans Affairs Medical Center, Emory University School of Medicine, Atlanta, Georgia. thomas.wingo@emory.edu
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wingo
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000453:epidemiology* / Q000235:genetics*; D001057:Apolipoproteins E; D015331:Cohort Studies; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D012307:Risk Factors
chemical_list: D001057:Apolipoproteins E