SUMMARY The cognitive impairment associated with neurodegenerative diseases like Alzheimer's disease (AD) is the major cause of disability in older adults. Epidemiological and clinical evidence suggests a strong link between cardiovascular disease (CVD) and AD, supported by shared risk factors including hypertension, mid-life hypercholesterolemia, presence of the apo E4 allele, smoking, and type 2 diabetes mellitus. Together, CVD and AD are the most important causes of morbidity and mortality in the elderly and represent a major public health and financial burden. It is well known that the atherosclerotic lesions leading to CVD and the brain pathologies progressing to dementia and AD start decades before the appearance of the clinical signs and symptoms of these diseases. While much has been learned about the macro- and micro-pathologic alterations of the brain in fully-developed late-stage AD, very little is known about the molecular and metabolic changes leading to the initial stages of neurodegeneration in AD and the associated gene expression and pathologic alterations. Current animal models of AD are transgenic or knockout rodents and, while the use of these animal models has advanced our understanding of some of the molecular aspects of AD, an important limitation is that overexpression or absence of specific disease-related genes does not always mimic the full spectrum of the disease in humans. The current proposal addresses the current need to identify animal models of neurodegenerative disease, where the pathology is induced in a manner similar to humans and not by genetic mutations. The objectives of this proposal are to identify the early brain gene expression and metabolic pathways affected by diet-induced CVD and associated brain cell pathology. In order to address these objectives, this proposal will utilize as experimental model the Ossabaw minipig, which we have recently shown to be an excellent model of diet-induced CVD. Specifically, Ossabaw minipigs develop coronary atherosclerosis when fed a human Western-style diet but not when fed a Mediterranean-style diet. Aim 1 will identify the changes in pig brain vascular and tissue gene expression pathways associated with diet-induced CVD using transcriptomic analysis. Aim 2 will identify the changes in pig brain metabolic pathways associated with diet-induced CVD using untargeted metabolomics and targeted lipidomics. Aim 3 will characterize the brain tissue and vascular histopathological alterations associated with diet-induced CVD using immunohistochemistry analysis. Through these aims, we will test the hypothesis that regulatory networks in endothelial dysfunction, inflammation and mitochondrial function serve as initiators in the cascade of metabolic and gene expression changes induced in the brain by diet-induced CVD. The knowledge gained on the initial triggers of neurodegeneration will lead to the identification of potential targets for early therapeutic interventions.