1. Epidemiological and clinical studies suggest that women may obtain cognitive benefits from oestrogen-replacement therapy (ERT) during menopause transition rather than in the post-menopausal stages. However, the underlying mechanisms remain to be determined. 2. We propose that long-term oestrogen deficiency may result in abnormal distribution and localization of brain oestrogen receptors, brain mitochondrial dysfunction, septohippocampal cholinergic degeneration and reactive gliosis. These multiple pathogenic factors may account for the lack of any beneficial effects of ERT in post-menopausal women with or without Alzheimer's disease.