Estrogen receptor α and APOEɛ4 polymorphisms interact to increase risk for sporadic AD in Italian females


Marco Racchi PhD, Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy (tel.: +39 0382 987738; fax: +39 0382 987405; e-mail:


Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects both sexes, with a higher prevalence in women. Declining estrogen levels after menopause may render estrogen target neurons in the brain more susceptible to age or disease-related processes such as AD. To investigate the role of two single nucleotide polymorphisms in the first intron of the ER-α gene, denominated PvuII and XbaI, and their interaction with the known AD susceptibility gene APOE, we examined 131 patients with sporadic AD and 109 healthy control subjects. In multinomial logistic regression analysis, a significantly increased risk of sporadic AD because of interaction between the ER-α p allele and APOE ɛ4 allele was observed in women, taking subjects who had neither the p allele nor ɛ4 as reference [odds ratio (OR) 7.24; 95% CI, 2.22–23.60]. For women carrying the ER-α x allele together with APOE ɛ4, the risk of sporadic AD was similarly elevated (OR 8.33; 95% CI, 1.73–40.06). The data suggest that the p and x alleles of polymorphic ER-α gene interact synergistically with the APOE ɛ4 allele to increase the risk of AD in women but not in men in this Italian cohort.