Abstract Numerous studies have demonstrated the clinical significance of identifying not only presence of carotid occlusive disease but also atherosclerotic plaques that are biochemically or functionally likely to produce emboli for identifying at-risk subjects. We have previously demonstrated that our vascular biomarkers, namely carotid strain indices enable detection of unstable plaque at risk for embolization and thereby mild cognitive impairment (MCI) which could then rapidly progress to Alzheimer disease (AD) and Alzheimer related dementias (ADRD). In this supplement we propose to obtain preliminary data to further evaluate vascular relationships to AD/ADRD using our strain indices to identify unstable plaque and pre-clinical atherosclerosis that may lead to MCI using carotid intima-media thickness (CIMT). In our first Aim, cognitive testing, transcranial Doppler (TCD), transcranial color-coded Doppler (TCCD) and Lagrangian carotid strain imaging (LCSI) will be performed on both carotid endarterectomy (CEA) patients and a control group of at-risk volunteers. These results will be validated and complimented by three- dimensional (3D) carotid magnetic resonance imaging (MRI). In addition, we will also compare strain indices, microemboli, cerebral hypoperfusion to the ground truth, namely 3D histopathology of the excised plaque. Our prior results demonstrate that both asymptomatic and symptomatic CEA patients present with an inverse relationship between strain indices and executive cognitive function. We hypothesize that this is due to silent strokes and microemboli contributing to a decline in executive function. Symptomatic CEA patients also demonstrate decline across other cognitive domains such as memory, visuospatial and language. Our second Aim, will focus on pre-clinical atherosclerosis, on the same group of high-risk volunteers with controls being age and gender matched volunteers. We will correlate CIMT measurements to TCD, TCCD and vascular strain indices on this cohort to cognitive testing for possible MCI. Baseline CIMT has been demonstrated to be predictive for developing cognitive impairment and poor executive function in a prior study which can then progress to AD. Our results will enable assessment of variations in plaque deposition and vascular stiffness to determine deviations that could establish vascular aging criteria. Interventions to reverse vascular aging for example lifestyle modifications and common medical therapies can then be prescribed. Validation of our results will foster use of real-time noninvasive ultrasound as a screening tool for identifying human subjects susceptible to developing mild vascular cognitive impairment that could lead to AD.