PROJECT SUMMARY Alzheimer’s disease (AD) is a prevalent disease with little understanding into the underlying mechanisms behind the development of the disease. Diastolic dysfunction has been shown to be an independent risk factor for the development of cognitive impairment. Patients with both diastolic heart failure (dHF) and AD represent a population where therapeutic options are highly needed, but which unfortunately have minimal therapeutic options due to a poor understanding of both diseases. Vascular dysfunction has been implicated in dHF and AD. Due to a chronic inflammatory state, vascular endothelial dysfunction can occur, driving dHF/AD pathologies. But little is known regarding the vascular endothelial mechanisms that contribute to cognitive impairment. Specifically, adenosine kinase (ADK) plays an important role in regulating blood flow under hypoxic conditions largely via its receptors (A1R, A2A/A2BR, and A3R). Pathologically, increased ADK is implicated in neurodegenerative diseases, but its role in the vascular contributions underlying dHF/AD pathologies is unknown. Thus, I hypothesize that augmented ADK activity impairs, whereas ADK inhibition restores, cerebral parenchymal arteriole vasodilator function, mitigating the dHF-induced worsening of cognitive decline and AD-related pathological outcomes. The goal of this project is to examine the role of adenosine kinase in vasodilator function in a mixed dHF and AD pathology and to further elucidate the underlying mechanisms of endothelial ADK in vasoreactivity. I will study this through the following two Specific Aims. Aim 1. Test the hypothesis that increases in cerebrovascular ADK activity impair vasodilator function of parenchymal arterioles, worsening cognitive dysfunction in mixed dHF/AD pathologies. Aim 2. Test the hypothesis and mechanisms by which cerebrovascular endothelium-selective deletion of ADK restores vasodilator function of small parenchymal arterioles in mixed dHF/AD. Through these aims, I will be able to better elucidate the underlying vascular contribution in mixed dHF and AD pathologies as well as mechanistically probe for the role of ADK in microvascular dysfunction and eventual cognitive impairment.