Atrial Fibrillation as a Determinant of Brain Health: Multimodal Evidence Supports Stroke-Dependent and Stroke-Independent Effects

Background and Aims Atrial fibrillation (AF) is associated with dementia and cognitive decline; it remains unclear whether the association is independent of cardiovascular comorbidities, particularly stroke. We aimed to establish stroke-dependent and stroke-independent effects of AF on multiple layers of brain health. Methods We investigated stroke-dependent and stroke-independent associations of AF with brain MRI imaging measures, cognitive performance, incident dementia, and biomarkers of neuronal and glial injury among 502 099 participants in the UK Biobank. Genetic analyses were performed to support causal inference. Results AF was associated with lower global and regional grey matter volume. After full adjustment, AF remained associated with lower grey matter volume (-0.13 SD, 95%CI: -0.15 to -0.10), greater white matter hyperintensity burden (0.06 SD, 0.03 to 0.10), and higher mean diffusivity (0.06 SD, 0.03 to 0.10). Genetic analyses were consistent with stroke-independent associations between AF and grey matter loss. AF was associated with poorer cognitive performance and higher concentrations of neurofilament light chain, a marker of neuronal injury. Associations with vascular and all-cause dementia were attenuated by adjustment for cardiovascular risk-factors and stroke. Genetic analyses supported ischaemic stroke as a major driver of dementia risk in AF. Conclusion Associations with grey matter and cognitive impairment persisted after accounting for stroke, whereas the association with dementia was largely explained by ischaemic stroke. This highlights the potential for AF to impact brain health through both stroke-dependent and stroke-independent mechanisms; stroke prevention is necessary but may not be sufficient to fully address the broader burden of AF-associated brain injury.