Previous evidence indicates that, in carriers of apolipoprotein E4 (ApoE4), estrogen therapy increased the risk of late-onset Alzheimer's disease (AD), whereas in individuals carrying ApoE2/3, estrogen therapy reduced the risk of AD [Cauley JA, Zmuda JM, Yaffe K, Kuller LH, Ferrell RE, Wisniewski SR, Cummings SR (1999) J Bone Miner Res 14:1175-1181; Yaffe K, Haan M, Byers A, Tangen C, Kuller L (2000) Neurology 54:1949-1954]. Estrogen mechanisms of action are mediated by two estrogen receptors (ERs), ERalpha and ERbeta. In this study, we determined the relationship between ER subtype and estrogen regulation of ApoE expression in HT-22 cells ectopically transfected with ERalpha or ERbeta, in primary cultured rat hippocampal neurons in vitro and in rat hippocampus in vivo by both molecular biological and pharmacological analyses. Results of these analyses demonstrated that activation of ERalpha either by 17beta-estradiol or a specific-agonist, propylpyrazole triol, up-regulated ApoE mRNA and protein expression. In contrast, the ERbeta-selective agonist, diarylpropionitrile, down-regulated ApoE mRNA and protein expression. These results demonstrate that, in vitro and in vivo, ApoE expression can be differentially regulated depending on activation of ER subtypes. These data suggest that use of ER-selective ligands could provide therapeutic benefit to reduce the risk of AD by increasing ApoE expression in ApoE2/3 allele carriers and decreasing ApoE expression in ApoE4 allele carriers.