PROJECT SUMMARY / ABSTRACT With the growing social and economic impact of dementia on the society, the emphasis is shifting from early diagnosis and treatment to the prevention of cognitive impairment and dementia. The social and economic implications of this epidemic will be greatest in women because of their longer life expectancy and elevated risk for dementia compared to men. Neuroprotective effects of estrogens offer the possibility of preventing or delaying mild cognitive impairment and dementia in postmenopausal women. However, oral conjugated equine estrogen treatment in older women who were more than a decade past their menopause did not prevent dementia, and there is controversy as to whether or not estrogen can preserve neurological function and decrease the risk of dementia when administered early in menopause defined as the ?critical window?. This project is proposed as a continuation to the Kronos Early Estrogen Prevention Study (KEEPS), a nationwide, multi-center, randomized blinded study of menopausal hormone therapy in newly postmenopausal women. Our objective is to assess the long-term risks and benefits of menopausal hormone therapy on Alzheimer's disease pathophysiology, cerebrovascular lesion load, cognitive and mood health in women who were treated with transdermal 17?-estradiol and oral conjugated equine estrogen compared to placebo within 36 months of their last menses; hypothesized as the ?critical window? for menopausal hormone therapy. Furthermore, we will investigate whether the Alzheimer's disease risk allele APOE ?4 and vascular risk factors influence the differences in A? deposition, brain structure, and cognition between each of the menopausal hormone therapy formulations and placebo, in order to provide insight into the mechanisms of cognitive and imaging biomarker changes associated with early menopausal hormone therapy. This project addresses an important and controversial problem regarding whether two commonly-used formulations of menopausal hormone therapy, administered during immediate postmenopausal years preserves cognition, neuronal integrity, and protects against cerebrovascular and Alzheimer's disease-related pathology. It is expected that the findings will hold the premise to significantly advance scientific knowledge and clinical practice by providing insight into the effects of early menopausal hormone therapy on long-term cognitive health.