Background: The epsilon4 allele of the apolipoprotein E ( APOE) gene is a major genetic risk factor for Alzheimer's disease but appears to be associated with greater risk in women than in men. Some studies suggest that the level of APOE may of its own modulate the risk for Alzheimer's disease. Sex differences and an apparent benefit of oestrogen therapy suggest a role for oestrogen. APOE expression is influenced by oestrogen and oestrogen therapy may not benefit women bearing an APOE epsilon4 allele. These findings suggest an interaction between oestrogen and APOE in the Alzheimer's disease process. Aim: To explore the hypothesis that APOE expression is regulated by a genomic mechanism and is modified by the polymorphisms in APOE associated with risk for Alzheimer's disease. Methods: In vitro binding studies were undertaken between oestrogen receptors and fragments of the human APOE gene. APOE gene expression was studied to investigate a possible functional interaction. Results: APOE epsilon2/epsilon3/epsilon4 coding and - 219 G/T promoter polymorphisms influenced binding to the oestrogen receptor and altered transcriptional activity in response to oestrogen. Conclusions: An allele dependent modulation of oestrogen induced regulation of APOE might be involved in the increased risk for Alzheimer's disease in women bearing an epsilon4 allele.