Autosomal recessive causes likely in early-onset Alzheimer disease

Arch Neurol. 2012 Jan;69(1):59-64. doi: 10.1001/archneurol.2011.221. Epub 2011 Sep 12.

Abstract

Objectives: 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.

Design: 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.

Setting: The Uniform Data Set, whose participants were collected from 32 US Alzheimer's Disease Centers, maintained by the National Alzheimer's Coordinating Center.

Participants: Individuals with probable AD and detailed parental history (n = 5370).

Main outcome measures: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Age of Onset
  • Alzheimer Disease / epidemiology*
  • Alzheimer Disease / genetics*
  • Apolipoproteins E*
  • Cohort Studies
  • Family Health*
  • Female
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Risk Factors

Substances

  • Apolipoproteins E