PROJECT SUMMARY Dementia poses a significant public health problem, and over 2 million American stroke survivors suffer from dementia. Atrial fibrillation (AF), which is a particular type of irregular heartbeat, is the most common cause of cardioembolic stroke, and studies have demonstrated that, among stroke patients, cardioembolic stroke patients are at the greatest risk for cognitive decline. However, AF, even independent of clinical stroke, has been associated with cognitive decline and dementia. The mechanisms linking AF and cognitive impairment are likely multifactorial, but the cerebral pathology that underlies this independent pathway between AF and dementia, apart from clinical stroke, is poorly understood. It is known that the cerebral pathology that leads to dementia precedes the development of clinical symptoms, suggesting that such pathology may already be present in patients with AF, but without prevalent dementia. Rapid developments in the dementia field have led to the ability to use blood-based (plasma) biomarkers, rather than the previous, more invasive, techniques, such as a lumbar puncture, to determine the presence of disease-causing pathology that contribute to the development of clinical Alzheimer’s disease (AD). Such plasma biomarkers of AD pathology include phosphorylated-tau181 (pTau181), plasma beta Amyloid (Aβ42/Aβ40) and neurofilament light (NFL), which has been suggested as the three primary pathologic components (A/T/N; Amyloid/Tau/Neurodegeneration) by which to guide AD-specific research. In this proposal, we aim to (Aim 1) compare the mean level of AD- associated plasma biomarkers (p-tau181, Aβ42/Aβ40, NFL) in a cohort of stroke-free, non-demented, high-risk cardiovascular (CVD) outpatients with AF to those in a control group of high-risk CVD patients without AF. We also will determine the potential for differences in the levels of these biomarkers based on characteristics of the AF patient, such as the type of AF a patient has or the possibility of an anticoagulation (AC) associated treatment effect. Finally, (Aim 2) we will determine in a sub-set of those patients if AD associated brain atrophy is present in CVD patients with AF versus in control patients without AF, accounting for silent cerebrovascular disease. This proposal embodies the goals of the R21 high-risk, high-reward grant mechanism by representing an innovative project that will begin to establish an understanding of the cerebral pathology in AF patients underlying the associated risk for cognitive decline, distinct from prevalent clinical stroke. It also has the potential for great public health impact by facilitating future research on potential targets to prevent, postpone or treat AF-related dementia.