The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER)alpha, and ERP mRNA were investigated in rat brain. Estradiol-17 beta (E-2) treatment following OVX reduced the levels of ER alpha mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreactive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ER alpha. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid beta were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E-2. ER alpha cDNA transfected PC 12 cells elaborated Inore neurite-like processes with E-2. In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD. (C) 2001 Elsevier Science Ltd. All rights reserved.