Across 502,099 UK Biobank participants, atrial fibrillation (AF) independently associated with reduced global grey matter volume (−0.13 SD), greater white matter hyperintensity burden (+0.06 SD), elevated mean diffusivity (+0.06 SD), poorer cognitive performance, and higher neurofilament light chain — a blood biomarker of neuronal injury — even after full adjustment for cardiovascular comorbidities and stroke history. Mendelian randomization analyses supported causal, stroke-independent pathways to grey matter loss, while ischaemic stroke emerged as the dominant driver of dementia risk in AF patients.
This preprint, not yet peer-reviewed, carries substantial implications for the roughly 60 million adults worldwide living with AF. Current management — anticoagulation and rate/rhythm control — is primarily stroke-focused. These findings suggest stroke prevention, while essential, may be insufficient to fully protect the AF brain. The stroke-independent mechanisms remain speculative but could include cerebral microembolism, systemic inflammation, reduced cardiac output causing chronic cerebral hypoperfusion, or autonomic dysregulation. Elevated neurofilament light chain hints at ongoing axonal damage even in clinically silent presentations. The genetic analyses strengthen causal inference, moving this beyond the observational confounding critique that has dogged earlier AF-cognition studies. Limitations include the UK Biobank's healthy volunteer bias and cross-sectional MRI data preventing temporal sequencing. Still, the scale and multimodal design — integrating imaging, biomarkers, cognition, and genomics — make this one of the most comprehensive AF-brain analyses to date. If confirmed after peer review, it argues for dedicated neuroprotective trials in AF independent of stroke endpoints.
