Familial aggregation in Alzheimer dementia-I. A model for the age-dependent expression of an autosomal dominant gene

An autosomal dominant genetic etiology has been proposed for Alzheimer Dementia (AD), but many cases appear to be sporadic. Evaluation of the possible genetic transmission of AD from its familial aggregation requires consideration of (1) the proportion of index cases with genetic disease, and (2) the consequences of typically very late onset. To investigate these factors, a provisional biomathematical genetic model was developed from the empirical age-specific incidence of AD in relatives. Based upon the premise of an autosomal dominant AD gene in proband families, the modeling technique provides estimates of the proportion of genetic index cases (as opposed to phenocopies) and the parameters of age-dependent gene expression. With appropriate parameters the model accurately reflects the age-specific familial risk of AD, suggesting the appropriateness of its underlying assumptions. The estimated proportions of genetic index cases suggest that heritable disease constitutes a majority of AD. In cases ascertained by the presence of aphasia or apraxia the estimated proportion of genetic cases is 100%. The greatest likelihood of gene expression is in the ninth decade, however, suggesting that most genetically predisposed relatives will die from other causes before developing AD.