Midlife obesity is associated with earlier onset of Alzheimer’s disease (AD) and increased AD neuropathology. Diets high in the saturated fatty acid palmitic acid (PA; C16:0) are a major contributor to obesity. They also potentiate neuroinflammatory diseases and exposure to dietary saturated fatty acids prime microglia (brain immune cells) towards an inflammatory phenotype. Because neuroinflammation and microglial activation are factors implicated in the etiology of AD we hypothesize that proinflammatory priming of brain microglia exacerbates AD pathology and increases accumulation of amyloid beta (Aβ) plaques characteristic of AD. If confirmed, this biological model could elucidate targets for primary and secondary prevention of AD. For the current study we propose use of a high-saturated fat diet to trigger a proinflammatory state in transgenic mouse models of AD, and to test whether stimulation of microglial proinflammatory pathways contributes to AD pathogenesis and progression. Microglia are key mediators of neuroinflammation and directly link diet with brain health. In the brain the fatty acid binding protein 4-uncoupling protein-2 (FABP4-UCP2) axis mediates proinflammatory effects of saturated fatty acids. Modification of the FABP4-UCP2 axis is a potential mechanism by which high fat diet exacerbates neuroinflammation and AD pathology. We hypothesize that proinflammatory priming by high fat diet in brain microglia exacerbates AD pathology and increases accumulation of amyloid beta (Aβ). The overall objective is to test the pathogenic role of the FABP4- UCP2 axis in AD in presence and absence of a proinflammatory trigger (high-fat diet). To provide a mechanistic understanding of how the FABP4-UCP2 axis perturbs microglial metabolic adaptation and exacerbates AD, we propose the following We propose the following Specific Aims to test our hypothesis: Aim 1) Determine the role of HFD and FABP4 on AD pathology in mouse models of Alzheimer’s (APPswe/PS1ΔE9 and APPswe/PS1ΔE9/FABP4flox/Tmem119CreERT2); and Aim 2) Determine biochemical and pharmacological effects of HFD and FABP4 on neuroinflammation in mouse models of AD. We will evaluate the role of the microglial FABP4-UCP2 axis in exacerbation of AD pathology. This targeted approach investigating diet-induced cognitive impairment will identify pathways and clinical targets for treatment of chronic proinflammatory diseases such as metabolic syndrome that increase the risk of AD. Significance to Veterans Health Care: Our approach is novel in that it will use a transdisciplinary approach (nutritional biochemistry neuroscience and pharmacology) to define interactions of diet in aging, metabolic disease, neuroinflammation, and AD. As underserved populations are at higher risk for developing obesity and AD, the broader long-term impact of this work is that our experiments will lead to better treatment options for at risk communities.