Neuroprotective effects of estrogens offer the possibility of preventing or delaying Alzheimer's disease in menopausal women. Estrogen treatment in older women who were late into menopause in the Women's Health Initiative Memory Study, did not prevent dementia. The question remains as to whether or not estrogen can preserve neurological function and decrease the risk of dementia when administered early in menopause from 6-36 months of the last menses. This project is proposed as an ancillary to the Kronos Early Estrogen Prevention Study (KEEPS), which is a nationwide, multi-center, randomized blinded study designed to provide evidence on the benefits and risks of oral and systemic estrogen treatment in recently menopausal women. Our goal is to test the neuroprotective effects of estrogen treatment in early menopause, during the 48 months of the randomized clinical trial. We will determine the rates of hemispheric atrophy on MRI, and the change in neuronal metabolite N-acetylaspartate (NAA) on proton MR spectroscopy (1H MRS) as a surrogate for the neuroprotective effects of estrogen treatment during the early postmenopausal years. In addition to the longitudinal serial measurements of whole brain, hippocampal and ischemic lesion volumes, we will use exploratory 3-dimensional voxel-based analysis of the serial MRI to determine the differences in the change in whole brain morphology in women who are taking estrogens compared to placebo. Our collaboration with the investigators of the KEEPS Cognitive and Affective Study will give us the ability to relate the change in neuronal metabolic integrity and brain morphology with the concurrent change in cognitive function in newly menopausal women. As an outcome of the proposed investigations, we expect to determine whether or not oral and transdermal estrogen treatment preserves brain structure and neuronal function during the immediate years after menopause. Several decades of follow-up are necessary to determine if estrogen treatment in newly menopausal women prevents Alzheimer's disease. This project will provide the necessary in vivo evidence on the neuroprotective effects of oral and transdermal estrogens in early menopause in the short term, for future large-scale, long term trials. The original contributions of this study to women's health research will include the demonstration of the effects of estrogens on longitudinal change in brain morphology and neuronal integrity, and the relationship between these biological changes and the concurrent change in cognitive function in recently menopausal women. PUBLIC HEALTH RELEVANCE: This study will provide evidence on the neuroprotective effects of estrogens with non-invasive imaging markers of structural and functional neuronal integrity in newly menopausal women, during a hormone treatment trial. This evidence would potentially have a significant impact on women making the decision to use hormone treatments for dementia prevention as they transition into menopause.