Background: Alzheimer's disease (AD) is associated with a polymorphism of the apolipoprotein E (ApoE) gene. Recently, an intronic polymorphism of the presenilin-1 gene on chromosome 14 was observed to be associated with AD. However, this finding has been challenged by subsequent studies. The present study examined whether the presenilin-1 polymorphism contributes to the observed familial aggregation in AD. Method: In a regional family study, 507 families were examined for the presence of AD and other psychiatric disorders. The role of genetic risk factors for the development of AD (i.e., ApoE and presenilin-1 polymorphisms) was assessed. Results and Conclusion: The presence of an ApoE ε4 allele was associated with AD. Relatives of subjects with at least one ApoE ε4 allele had increased risks for developing dementia. However, familial aggregation of AD was only partially attributable to the presence of an ApoE ε4 allele. The intronic polymorphism of the presenilin-1 gene could only explain a minor proportion of familial AD, predominantly that with late onset of the disease.