ABSTRACT Atrial fibrillation (AF) is the most common, costly cardiac arrhythmia affecting over 6 million people in the U.S. with a 2-fold increase in mortality. A major public health problem, AF has serious consequences of stroke and heart failure, and is an independent risk factor for mild cognitive impairment (MCI) and Alzheimer’s-type dementia (AD). Mechanisms of AF-related MCI/AD remain unclear, but possible multifactorial mechanisms include cerebral hypoperfusion, subclinical cerebral ischemia, vascular inflammation, hippocampal brain atrophy, or genetic factors. Improved use of oral anticoagulant (OAC) medications could theoretically reduce subclinical cerebral ischemia, but research on how, or if, OACs effect the rate of progression of cognitive decline has shown conflicting results. While OACs can decrease cerebral ischemia, these drugs increase the risk of cerebral hemorrhage also associated with cognitive decline. There are newer OAC drugs that reduce rates of cerebral ischemia and hemorrhage better than warfarin called non-Vitamin-K inhibitors (NOACs). The goal of the proposed research is to examine the rate of progression of cognitive decline (using neuropsychological and functional testing scores) in patients with AF compared to those without AF in the NIH-sponsored National Alzheimer’s Coordinating Center (NACC) dataset. This longitudinal study with approximately 42,000 community-dwelling adults includes subjects with a range of cognitive impairment (normal, MCI, and dementia). One major methodological problem in prior AF-related MCI/AD studies is inconsistent utilization of the variety of neuropsychological measures that the NACC database includes. We will also compare rate of cognitive decline in AF patients on OAC to those not on OAC and those on NOACs versus warfarin. Additionally, we will explore AD neuropathology (i.e., neurofibrillary tangles), vascular dementia, and mixed AD in AF patients versus those without AF using NACC autopsy data. Women are at higher risk than men of MCI and AD, which is also true of AF-related stroke, indicating significant contribution of sex as a biological variable. The NACC database provides a unique and rich opportunity to examine AF and OAC effects on rate of progression from normal cognition to MCI to AD. Understanding more about AF-related cognitive dysfunction is critical to its successful management and the development of targeted therapies to prevent or slow cognitive decline. This pilot study will provide data for a larger R01 to combine imaging, PET, and Tau biomarkers to examine a variety of types of cognitive impairment in patients with AF.