Autosomal recessive causes likely in early-onset Alzheimer disease.

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.