Background: The interrelationships between atrial fibrillation (AF), brain lesions and cognitive function are poorly understood. We aimed to investigate the relationship of AF with brain lesions and cognition.

Methods: We enrolled 1,480 patients with and 959 without AF in a multicenter prospective study (Swiss-AF; NCT02105844). We assessed brain structure, and cognition using the Montreal Cognitive Assessment (MoCA). Brain magnetic resonance imaging (MRI) was performed to assess large non-cortical and cortical infarcts (LNCCI), small non-cortical infarcts (SNCI), white matter hyperintensities (WMH), and microbleeds. Using causal mediation analyses, we investigated the direct (lesion-independent) and indirect (lesion-mediated) effects of AF on cognition.

Results: Mean age in AF patients is 75.0 vs. 74.2 years in no-AF patients, 28.6% vs. 36.9% are female, and comorbidities are comparable. The prevalence of MRI-detected brain infarcts (LNCCI and/or SNCI) is 40.1% in AF patients vs. 24.0% in no-AF patients, adjusted OR (95% CI): 1.78 (1.30; 2.44), p = 0.0003. WMH (Fazekas ≥2) are more prevalent in AF patients (59.2% vs 44.4%), adjusted OR (95% CI): 2.03 (1.50; 2.77), p = 4.6e-06. The mean MoCA score is 25.3 in AF patients and 26.4 in no-AF patients. In mediation analysis, the total effect of AF on cognition is -1.05 MoCA points, decomposed into a direct effect of -0.99 and an indirect, lesion-mediated, effect of -0.06 points.

Conclusions: The prevalence of ischemic brain infarcts and WMH is higher in patients with AF than without AF despite comparable comorbidities. AF is associated with lower cognitive function, primarily through a direct effect rather than mediated by brain lesions.