PROJECT SUMMARY/ABSTRACTThere is growing need to understand mechanisms and treatment options associated with vascular contributionsto Alzheimers disease (AD) and other forms of dementia and cognitive dysfunction. Early brain changesassociated with AD and other forms of cognitive dysfunction such as white matter lesion (WML) burdenhypoperfusion and metabolic mismatch have vascular risk factors (hypertension diabetes aging and smoking).Such structural and functional brain changes are often considered secondary to intracranial cerebral small vesseldisease. In contrast our preliminary data indicate that extra-cranial carotid artery disease (ECAD) contributesto brain pathology and its treatment with carotid endarterectomy (CEA) (to surgically remove the plaque)decreases accumulation of WMLs and neurofibrillary tangles increases structural connectivity and mostimportantly improves cognition.ECAD primarily signifies atherosclerosis of the carotid bifurcation where plaque accumulation is uniquelyprevalent compared to other cerebrovascular locations. Carotid arteries play a major role in brain physiologybecause they bring the majority of blood and nutrients to the brain. We hypothesize that mechanisms of ECADcontribution to Alzheimers disease and cognitive dysfunction are likely multifactorial and include embolicphenomena decreased blood flow and endothelial activation/inflammation. Interplay between these modifiablefactors and non-modifiable risks (ie age sex and ApoE status) likely contribute to neurodegeneration that canlead to cognitive dysfunction. Our Aims 1 and 2 use cross-sectional studies to evaluate potential mechanisms ofECAD contribution to AD-related brain structure and function changes. Subject evaluation includesneurocognitive testing and quantification of MRI-defined structural parameters WML accumulation Alzheimersdisease blood-based biomarkers and systemic cerebral and carotid markers of inflammation. Aim 3 employs aprospective controlled cohort study evaluating the treatment of ECAD with CEA to determine which patientsshow improved cognitive function (responders) and what factors are drivers of this response.This project will define quantifiable measures of brain structural changes leading to neurodegeneration andcognitive dysfunction in subjects with ECAD. This should further build the impetus for clinical trials that changemanagement of patients with ECAD. In addition our study offers the exciting opportunity to reveal novel insightsof early Alzheimers disease risk and specific mechanisms of vascular contributions. Understanding the uniquecontribution of ECAD to AD/cognitive dysfunction risk is particularly compelling because effectivetreatments exist for ECAD yet are not currently offered for the treatment/prevention of cognitivedysfunction.