Atrial fibrillation (AF) is the most common serious cardiac arrhythmia, affecting approximately 1-2% of the population (Go et al. JAMA. 2001;285:2370-5). AF is associated with endothelial damage, low cardiac output, and the presence of cerebral microemboli or microinfarcts (Kalantarian et al. Ann Intern Med. 2014;161:650-8) and emerging data indicate that AF may also increase the risk of dementia, independent of clinical stroke (de Bruijn et al. JAMA Neurol. 2015;72:1288-94). However, few studies have evaluated associations between AF and markers of cerebral small vessel disease, including structural brain volumes and domain-specific cognitive function. We ascertained a cohort of healthy elderly adults and patients with mild cognitive impairment (MCI) and Alzheimer’s dementia (AD) with and without comorbid AF from Phase 1 of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (N=505; mean age=75.9±6.4; median CHADS2 score=1.0; proportion with AF on anticoagulation=15.7%). Primary outcomes were MRI-derived brain volumetrics including global atrophy, indexed by brain parenchymal fraction (BPF), and white matter hyperintensity (WMH) burden, and standardized scores on domain-specific cognitive tests. Multivariable linear regression was used to evaluate associations between a history of cardiac arrhythmia, including AF, and volumetric and cognitive outcomes. All models were adjusted for age, sex, diagnostic classification, baseline score on the Mini Mental State Exam, apolipoprotein E (APOE4) status, CHADS2 score, and for history of prior clinical stroke. In elderly adults and patients with MCI and AD, a history of cardiac arrhythmias including AF was associated with a significant reduction in mean BPF (F=1.83, p=.03) and impaired performance on the Rey Auditory Verbal Learning Test (F=2.26, p=.03), and Trail Making Test B (F=2.09, p=.04), reflecting primarily verbal recognition and task-switching abilities, after adjustment for prior stroke. No associations were observed between AF and WMH burden or other standardized neuropsychological measures. AF is associated with brain atrophy and cognitive impairment independent of age, APOE4 status, and prior stroke (CHADS2 score). Trials evaluating structural and cognitive endpoints are required to determine the efficacy of treatments for AF for the prevention of progressive neurodegenerative and cognitive decline.