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.