Project 1 Summary Basic and pre-clinical research provides convincing evidence that estrogens exert neuroprotective effects in the hippocampus, a brain area critical for memory and vulnerable to effects of aging and Alzheimer’s disease. Thus, expectations were that menopausal hormone therapy would be neuroprotective and decrease the risk of Alzheimer’s disease and related dementias in women. However, the benefits of hormone therapy on the brain and cognition are unresolved. Whereas preclinical research is primarily conducted in models of healthy aging, clinical research often includes subjects with diverse health status. To reconcile this evidence gap, we will determine impacts of cardiometabolic status on the ability of estrogens to beneficially impact the hippocampal memory system. Our central hypothesis is that in aging females, cardiometabolic disease, due to associated dysfunction of the ubiquitin/proteasome system, disrupts the ability of estrogens to regulate levels of ERα in the hippocampus, regulation that is necessary for estradiol treatment to exert lasting positive effects on memory during aging. The hypothesis will be tested by the following specific aims: 1) determine if individual differences in the response to midlife estradiol treatment on the hippocampal memory system are associated with individual differences in cardiometabolic health; 2) determine if estradiol effects on the hippocampal memory system in aging females are impacted by obesity and impaired glucose regulation; and 3) determine if estradiol effects on the hippocampal memory system in aging females are impacted by cardiovascular disease. Experiments under the first aim will use a longitudinal study design and a rat model of midlife estradiol use—in which estradiol is administered either immediately after the cessation of ovarian function or after a delay—to assess relationships between measures of body fat accumulation, glucose regulation, cardiovascular function, hippocampal function, and memory from middle to old age. Experiments under the second aim will expose middle-aged female rats to a high-fat or control diet before or after the initiation of midlife estradiol treatment and a) assess the ability of midlife estradiol to exert effects on levels of hippocampal ERα, measures of hippocampal function, and memory; and b) determine if increasing levels of hippocampal ERα differentially affect memory and the hippocampus in aging females on high-fat or control diets. Experiments under the third aim will use an angiotensin II-dependent hypertensive rat model to a) assess the ability of midlife estradiol to exert effects on levels of hippocampal ERα, measures of hippocampal function, and memory; and b) determine if increasing levels of hippocampal ERα differentially affect memory and the hippocampus in aging females without or without hypertension. Results will determine under which conditions estrogen treatment provides beneficial effects to the hippocampally mediated cognitive trajectory, a determination with implications for the prevention or delaying of aging-associated memory disorders, including Alzheimer’s disease and related dementias.