Cognitive Impairment and Incident Atrial Fibrillation in Individuals without Stroke: Evidence from Two Prospective Cohort Studies and Mendelian Randomization Analysis

Aims Emerging evidence suggests that neurocognitive dysfunction may contribute to the pathogenesis of atrial fibrillation (AF). We aimed to investigate whether cognitive impairment precedes incident AF independent of stroke, and to explore the potential causal relationships within a brain–heart axis framework. Methods and results Included were 18,392 participants from the Kailuan study who completed the Mini-Mental State Examination (MMSE) and 377,248 participants from the UK Biobank who completed domain-specific cognitive tests. All participants were aged ≥ 45 years and were free of stroke, AF, other cardiovascular diseases, or cancer at baseline. AF cases were identified through electrocardiographic examinations or linkage to health records. Cox proportional hazards models were used to estimate associations between cognitive function and incident AF. Mendelian randomization (MR) analyses were further conducted to assess potential causal relationships. In the Kailuan study, cognitive impairment (MMSE <24) was associated with a higher risk of incident AF compared with normal cognition (MMSE ≥24) (adjusted hazard ratio (aHR):2.32, 95% confidence interval (CI):1.21, 4.45). In the UK Biobank, poorer performance in reasoning (aHR:1.21, 95% CI: 1.03, 1.43) and processing speed (aHR:1.23, 95% CI: 1.03, 1.47) was associated with a higher risk of new-onset AF. These associations remained robust after excluding incident stroke cases. MR analysis suggested that genetically predicted better reasoning ability was associated with a lower risk of new-onset AF. Conclusion Cognitive impairment independently predicts incident AF in stroke-free individuals. These findings provide evidence for a stroke-independent brain–heart axis that may contribute to AF development.