Genetic transmission of Alzheimer disease among families in a Dutch population-based study

We evaluated age at onset and transmission patterns of Alzheimer's disease (AD) in families of 198 patients who had onset of symptoms before the age of 65 years and were diagnosed before the age of 70 years. Patients were ascertained in a population based study in The Netherlands. The results suggest that the risk of AD by the age of 90 in first degree relatives is 39% (95% confidence interval 27 to 51). By the age of 90, this risk is 2.8 (95% confidence interval 1.5-5.2) times greater than the corresponding risk of 14% among relatives of age and sex matched control subjects. Segregation analysis indicated that patterns of familial clustering are best explained by transmission of a major autosomal dominant gene with reduced penetrance and a multifactorial component. However, the single major locus model could be rejected in favour of the mixed model only when a cohort effect for heritability was allowed for. The frequency of the AD susceptibility allele was estimated to be 0.48% in the single major locus model and 0.31% in the mixed model. Although our study confirms that a dominant major gene is implicated in early onset AD, the results suggest that other genetic or perhaps non-genetic factors may account for the disease in a considerable number of patients.