Background: There is a widespread belief that dominant mutations cause most cases of early-onset Alzheimer's Disease (onset ≤ 60 years, EOAD) yet epidemiologic evidence suggests they explain ≤ 10% of all EOAD cases. Objective: To determine the genetic contribution to the remaining ~90% of non-autosomal dominant EOAD cases and identify the likely mechanism of inheritance in those cases. Design, Subjects: A liability threshold model of disease was used to estimate heritability of EOAD and late-onset AD (LOAD) using concordance for AD among parent-offspring pairs. Individuals with probable AD and detailed parental history (n =5,370) were identified in the Uniform Dataset (UDS) whose participants were collected from 32 Alzheimer's Disease Centers. Results: For LOAD (n = 4,302), we found sex-specific parent–offspring concordance that ranged from ~10-30% resulting in a heritability of 69.8% (95% CI: 64.6–75.0%) and equal heritability for both sexes regardless of parental gender. For EOAD (n = 702), we found that the parent–offspring concordance is ≤ 10% and concordance among siblings is 21.6%. EOAD heritability is 92–100% for all likely values of EOAD prevalence. Conclusion: We confirm LOAD is a highly polygenic disease. By contrast, the data for EOAD suggest it is an almost entirely genetically based disease, and the pattern 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 ~90% of EOAD cases are due to autosomal recessive causes.