Retrospective analysis shows that women who took estrogen replacement therapy may have less risk of cognitive decline and of developing Alzheimer's disease (AD). The greater risk associated with female gender and these observations suggest that estrogen may be implicated in the aetiology of AD. Estrogen is one of a family of sex steroids that exerts many of its genomic effects through the activation of the nuclear estrogen receptors, ERalpha and ERbeta. Previously, increased risk for AD has been reported for polymorphisms in the ERalpha gene in a Japanese cohort, however, this association has not been systematically replicated. We have further investigated polymorphisms in the ERalpha and have extended this to investigate an association with a polymorphism within the ERbeta gene in an independent UK Caucasian population. We found no independent association of these polymorphisms with the risk of developing AD in the total sample nor within either gender. However, we did detect a significant interaction between the ERalpha and ERbeta polymorphisms and the risk for AD (OR=0.22 95% CI (0.05-0.88), P=0.02). If this finding can be supported in other independent studies, it may suggest that the risk for AD may be modulated only when both ERalpha and ERbeta have particular variations in their expression and/or biological activities.