Although several Alzheimer's disease (AD)-linked genetic mutations have been identified that directly cause the disease, these cases are rare relative to sporadic incidence. On the other hand, it is now clear that metabolic and environmental factors are largely responsible for the etiology of a majority of sporadic cases of AD and that the AD risk increases in subjects with vascular conditions including hypertension, diabetes and atherosclerosis. The overall goal of our research is to define cerebrovascular dysfunction as a mechanistic link between metabolic disorders and AD so that novel vascular-targeted therapeutics can be developed as AD treatment. The present project utilizes both non-genetic and transgenic (i.e., expressing mutant amyloid precursor protein) mouse models made either hyperlipidemic or type 2 diabetic by dietary regimen. These mice express AD-like cognitive impairment correlated with vascular dysfunction with or without accelerated amyloid deposition. We will take advantage of the known vasculoprotective properties of HDL/Apo AI (as in cardiovascular diseases) and test the efficacy of a novel Apo AI mimetic peptide i.e., 5A with demonstrated anti-atherogenic and anti-inflammatory effects in attenuating cognitive impairment in the two models. The outcome of these studies while providing a strong support to the vascular hypothesis of AD pathogenesis should further suggest novel vascular-based therapeutic strategies represented by the 5A peptide.