The preventive effect of estrogen on Alzheimer's disease (AD) has become clearer with many epidemiological reports. However, the therapeutic effects of estrogen have been controversial until now. In our trials, estrogen treatment showed a beneficial therapeutic effect for women with mild to moderate AD. Improvement of cognitive function was recognized during the third week from the beginning of administration and maintained as long as estrogen treatment continued. The longer the duration of HRT, the more HRT is useful for the prevention and therapy of AD. However, in most cases, administration of estrogen is discontinued because of the adverse effects on the uterus and breast. J 861 is a derivative of estradiol-17alpha, which has little effect on the sexual organs. The effects of estradiol-17beta (E2) and J 861 on neuronal function and vascular factors were investigated. J 861 was suggested to prevent both the intracellular calcium increase and peroxidation induced by amyloid beta (Abeta), more effectively than E2. The effect of J 861 may be related with both the direct non-genomic and the ER-mediated systems. J 861 showed neurotrophic effects like E2. J 861 inhibited the adhesion of monocytes to vascular endothelium, more effectively than E2. Also, J 861 suppressed the expression of adhesive factors, such as E-selectin and intercellular cell adhesion molecule-1 (ICAM-1), more effectively than E2.