PROJECT SUMMARY Obesity, inflammation and cerebral microvascular dysfunction are highly interdependent risk factors for Alzheimer’s disease. However, the mechanistic understanding of how these risk factors interact to influence the progression of Alzheimer’s is limited. This gap will be addressed by the current administrative supplement. Preliminary data and published studies from the applicant’s lab show that outside of the brain, macrophages are the dominant inflammatory mediator driving microvascular dysfunction in obesity. Intriguingly, macrophages are also present within the brain, where they are localized to the perivascular space surrounding the penetrating arterioles of the cerebral microvasculature, although their contribution to vascular function and Alzheimer’s progression is poorly defined. The current objective is to assess how perivascular macrophages are involved in the interaction between obesity and Alzheimer’s. The objective will be accomplished by testing the central hypothesis that obesity-dependent inflammation contributes to the progression of Alzheimer’s disease by increasing cerebral microvascular dysfunction. Two specific aims are proposed: aim 1 will define how obesity and inflammation contribute to cerebral microvascular dysfunction in Alzheimer’s Disease, and aim 2 will define how perivascular macrophages contribute to Alzheimer’s Disease pathology. Diet-induced obesity will be studied in a transgenic mouse model of Alzheimer’s. The interaction between obesity, inflammation and the cerebral microvasculature will be assessed in both male and female animals using macrophage phenotype analysis, macrophage depletion studies, in vivo deep brain imaging microscopy, and in vitro functional assays of freshly isolated penetrating arteriolar segments. Completing these aims will address the question of why obesity is a risk factor for Alzheimer’s disease by establishing a new mechanism in which inflammation exacerbates Alzheimer’s through macrophage-dependent cerebral microvascular dysfunction.