The role of estrogen in the aging brain is an active area of research, as age-related decreases in circulating estrogen have been associated with cognitive dysfunction. The precise biological mechanisms by which alterations in estrogen lead to cognitive changes remain unclear. This study will used advanced neuroimaging and genetic techniques to investigate the ways in which alterations in amount of or response to estrogen affect the brain, with implications for understanding the function of neural estrogen in health and disease. Two distinct clinical populations will be studied in order to address multiple aspects of this question. First, utilizing data from an existing cohort of older adults consisting of healthy controls and patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD), we will assess the contribution of genetic variation in the estrogen pathway genes ESR1 (estrogen receptor 1), ESR2 (estrogen receptor 2), and CYP19A1 (aromatase), to alterations in brain morphology, including regional volumes, gray matter densities, and cortical thicknesses. We will examine the interaction of such morphologic changes with gender, disease status (AD, MCI, or healthy control), and APOE 54 gene carrier status. The second component of this study will focus on breast cancer patients, as this is a population that undergoes treatment-related hormonal changes. We will examine the influence of chemotherapy-induced menopause, aromatase inhibitor therapy, and selective estrogen receptor modulator therapy on brain activation during a working memory task and brain perfusion at rest, and relate neural changes to changes in memory function. Both clinical populations studied have relevance to the cognitive dysfunction observed in association with decreased estrogen in age-related conditions and breast cancer. The proposed study, when completed, will contribute to our knowledge of estrogen's various and complex roles in the brain and cognition. This application consists of the research described above and a training plan encompassing one-on-one mentoring, small group meetings, seminar series, local and national meetings, collaborative opportunities, publication and presentation of results, and clinical work. We believe that completion of the proposed research and training plan will provide an excellent foundation for Ms. Conroy as she completes her M.D. and Ph.D. degrees and moves forward in her training as a physician-scientist. PUBLIC HEALTH RELEVANCE: The role of estrogen in the aging brain is an active area of research, as age-related decreases in estrogen have been associated with cognitive problems. This study will examine the effects of variation in estrogen-related genes on brain structure, and relate these effects to changes in memory function. We will also investigate how changes in estrogen as a result of breast cancer treatment alter brain function, and relate these changes to memory function.