Abstract of Proposed Research Administration of estrogens begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline and Alzheimer's disease (AD) and related dementias. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain, cognitive aging, and risk of dementia of short-term use of estrogens are unknown. The long-term goal of the research currently supported is to determine the consequences for the female brain and for female cognitive aging of short-term exposure to estrogens during middle-age such as that used by women during the menopausal transition. [Please see full abstract of current grant at the end of Research Strategy.] Our work has shown that short-term exposure to estradiol, the primary estrogen, following ovariectomy in aging female rodents provides lasting, likely permanent, cognitive benefits that extend well beyond the period of exposure and results in concomitant lasting, likely permanent increases in levels of estrogen receptor (ER) ? in the hippocampus, a brain area critical for memory. Furthermore, we have demonstrated that increased levels or availability of ERs in the hippocampus results in enhanced memory in the absence of ovarian or endogenously administered estrogens. The importance of ER? to cognitive aging is highlighted by results of studies that show a relationship between levels of wild-type and polymorphisms of ER? with development of cognitive impairment in women, including risk of AD. The currently proposed research aims to expand on our present work on female cognitive aging to include investigation of estradiol and estrogen receptor impacts on the hippocampus and memory in a new mouse model of AD, A? precursor protein (APP) knock-in mice, AppNL-G-F/NL-G-F. The model exhibits typical A? pathology and memory impairment in an age-dependent manner without APP overexpression, the strategy used in most of the other available mouse models of AD. We will specifically investigate the ability of estradiol treatments that we have shown to enhance hippocampal levels of ER? and memory to impact memory impairments and A? in these APP knock-in mice. Two specific aims will be tested: 1) To determine if manipulating estradiol levels in female APP knock-in mice before development of A? pathology can impact memory and / or pathology in the hippocampus; 2) To determine if manipulation of estradiol levels after development of pathology can impact function and / or further progression of A? pathology. Results of these pilot projects will provide the basis of our future investigation into how short-term midlife estradiol use impacts long-term risk for AD.