Objective:To investigate the molecular genetic mechanisms of cognitive dysfunction in elderly patients with atrial fibrillation.Methods:A case-control study was conducted to analyze statistical data from a previous epidemiological survey, which used a stratified, random cluster sampling method and covered towns and communities in eastern, southern and northern Xinjiang.A total of 8529 residents aged ≥60 years were investigated, of whom, 301 patients with a history of atrial fibrillation or a definitive diagnosis of atrial fibrillation by electrocardiogram during investigation were selected.The patients with atrial fibrillation were divided into a cognitive impairment group(55 cases)and a normal cognitive group(246 cases)according to the diagnostic criteria of cognitive dysfunction.Genotypes of a GWAS on the main atrial fibrillation-related genes were analyzed for genes associated with atrial fibrillation, aging and cognitive impairment.Results:Unconditional multivariate Logistic regression analysis showed that mental work and non-solitary living were protective factors against cognitive impairment in the elderly with atrial fibrillation( OR=0.206, 95% CI: 0.048-0.873; OR=0.286, 95% CI: 0.089-0.922; all P<0.05). Klotho(rs571118)TT and the ApoE ε3/ε4 genotypes were independent risk factors for cognitive impairment in elderly patients with atrial fibrillation( OR=3.922, 95% CI: 1.326-11.595; OR=6.843, 95% CI: 1.263-37.078; all P< 0.05). The interaction between Klotho(rs571118)and ApoE ε3/ε4 was not associated with cognitive impairment in the elderly with atrial fibrillation( OR=1.552, 95% CI: 0.703-3.428; OR=1.897, 95% CI: 0.967-3.723; OR=0.496, 95% CI: 0.061-4.026; all P>0.05). Conclusions:Klotho(rs571118)TT and the ApoE ε3/ε4 genotypes may promote cognitive dysfunction in elderly patients with atrial fibrillation.The results may serve as a basis for research on the mechanisms of cognitive dysfunction in elderly patients with atrial fibrillation.