ABSTRACT Atrial fibrillation (AF) is the most common sustained arrhythmia, currently affecting >33.5 million adults world- wide. Chronic kidney disease (CKD) is also highly prevalent and affects 14% of the U.S. and North American population. The burden of AF is 3-fold higher in CKD and affects up to 25% of CKD patients. AF is strongly associated with risk of ischemic stroke and death; and these risks are even higher in patients with CKD. Even in the absence of clinical ischemic stroke, some studies have suggested that AF is also associated with excess risks of all dementia types, including Alzheimer’s and vascular dementia, although definitive evidence is lacking. Alzheimer's disease is characterized by neurodegenerative changes in the brain, including amyloid depositions and neurofibrillary tangles. It is plausible that AF may lead to cerebral microinfarcts, cerebral hemorrhage and reduced cerebral blood flow, all which could promote Alzheimer’s disease and other dementias. Gaining a greater understanding of the association of AF with Alzheimer’s and other dementias is particularly important in the CKD population, in whom the incidence and prevalence of dementia is even higher compared with the general population; and in whom the cause of dementia remains elusive and thus largely untreated. Currently, data on the risk of dementia in patients with CKD and AF are limited and may provide new insight into the mechanisms that contribute to dementia in CKD patients. Further, data on whether treatment of AF mitigates risk of dementia are conflicting in all populations (regardless of CKD status). While there are some existing studies of treatment of AF and risk of dementia, most have limitations, including (1) a primary focus on anticoagulation and not a comprehensive evaluation of other AF therapies; (2) inclusion of selected populations and none with CKD; and (3) inadequate consideration of interim clinical measures that may affect receipt and outcomes of AF therapies. Therefore, the effects of successful treatment of AF on risk of dementia remains largely unknown. Further data could identify novel therapeutic approaches for the prevention and treatment of dementia. We propose to efficiently leverage our unique research platform that includes “real-world” contemporary data to evaluate the risk of dementia in patients with AF, with and without CKD; as well as determine whether successful treatment of AF with a comprehensive range of therapies is linked to a lower risk of dementia. To conduct this work, we will perform a rigorous comparative effectiveness analysis of >500,000 patients with and without AF from two participating health care systems in California. This proposed supplemental project will yield key insights to understanding the link between AF and dementia; particularly in the high-risk population of those with CKD. Furthermore, the anticipated results could form the basis of future randomized clinical trials.