PROJECT SUMMARY/ABSTRACT In the United States, at least five million elderly Americans suffer from dementias, and it is projected that the number of new dementia cases will double by 2025 due to the growth in life expectancy. Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and accounts for up to 80% of all dementia diagnoses. Currently, there is no cure for AD. Thus, there is an urgent need for novel interventions that can prevent onset and slow the disease progression, thereby improving the quality of life in the elderly. Apolipoprotein E4 allele (ApoE4) is the most prevalent genetic risk factor for AD and represents 60% of AD subjects in the general population, yet we do not fully understand how it causes dementia. ApoE protein is critical for lipid metabolism and cholesterol transport. The other known risk factors for AD include older age, female gender, and hypertension. Our robust preliminary data obtained from the human ApoE4-knockin (E4) and ApoE3-knockin (E3) mice, demonstrates that compared to the males, female E4 mice develop cognitive decline and hypertension with aging. Notably, we find CSF levels of angiotensin II (AngII), the excitatory component of the brain renin-angiotensin system (RAS), progressively increase with age in the female E4 mice. It is now becoming evident that the proinflammatory actions of AngII damage the blood-brain-barrier and increase amyloid-b and tau load causing neurotoxicity in spatial learning and memory region of the brain, the hippocampus (HC). Moreover, AngII acting via type 1 receptors in a cardiovascular region of the brain, paraventricular nucleus of hypothalamus (PVN), regulates arterial blood pressure and autonomic function. Thus, our central hypothesis is that brain RAS-driven inflammation mediates cognitive decline and hypertension in aging, in the ApoE4 genotype. A major concern has been the lack of appropriate murine models that recapitulate hallmarks of human AD. Hence we will study novel transgenic mice that express the human ApoE3 or ApoE4 knockin gene combined with three transgenes (APPSW, PS1dE9, and tauP301S) that model AD in the mice. We will test the novel hypotheses with state-of-the art physiological and molecular approaches in the following two specific aims. Aim 1: To test the hypothesis that brain RAS-induced inflammation drives cognitive impairment in female E4 mice. Aim 2: To test the hypothesis that hypertension exacerbates cognitive decline in female E4 mice with age. These studies will define underlying central mechanism(s) of cognitive decline in aging and identify novel therapeutic target(s) that will enable discoveries from basic science to be translated into clinical practice for Alzheimer’s disease and related dementias.