Cardiovascular disease has emerged as a significant contributor to cognitive impairment, operating both independently and as a catalyst for the progression of Alzheimer’s disease (AD) from low-grade to overt dementia. Amongst all vascular diseases, atherosclerosis stands out because of its prevalence as a common comorbidity in AD patients. Atherosclerosis impairs vascular brain function at multiple levels. First, by directly impacting the circle of Willis and carotid arteries, atherosclerosis leads to narrowing of the vascular lumen, reducing blood flow for the supported regions. Second, rupture of atherosclerotic plaques often leads to thrombosis, resulting in either vessel occlusion or thromboembolisms. Depending on the size of the embolus, it may cause lesions that range from “silent” infarcts or microinfarcts to large cerebral infarcts with overt clinical symptoms. Third, independent of plaques, its associated hyperlipidemia impairs endothelial and smooth muscle cell function in both systemic and brain vessels. Our investigations into the brain vasculature of mice at the onset of atherosclerosis revealed distinctive vulnerabilities and increased vascular pathology in those with AD amyloid pathology. At the cellular level, perivascular macrophages exhibited prominent alterations in density, distribution, and molecular profile. We also observed dysfunctional permeability, specifically affecting the cortex and hippocampus. Deficiencies in vascular contractility and glymphatic flow were more pronounced in mouse models of AD compared to similarly aged mice without AD pathology. Overall, the findings underscore the impact of atherosclerosis disease on the brain’s microvasculature and provide the underlying impetus to focus on the small vessel disease in response to metabolic lipid deregulation. Our underlying hypothesis posits that hyperlipidemia contributes to vascular dysfunction in both additive and synergistic manners to existing AD pathology. To delve deeper, we propose a comprehensive analysis encompassing structural, molecular, and functional aspects of the vasculature in the context of AD, utilizing two disease models of AD amyloidosis. Crucially, we will evaluate the secretome of endothelial, smooth muscle, pericytes and perivascular macrophages, capturing both intracellular and serum- released proteins as potential cell-specific biomarkers for disease progression. Furthermore, we aim to investigate whether correcting hyperlipidemia, either pharmacologically or by modifying the diet and reversing low-density lipoprotein receptor levels, can restore observed alterations. Correlating these interventions with AD severity will provide important insights into potential therapeutic avenues. In tandem, we plan to develop an integrated computational network that overlays multiple datasets in a spatiotemporal manner, establishing connections with AD pathology. This holistic approach seeks to deepen our understanding of the intricate relationships ...