Department of Cardiology Beijing Anzhen Hospital, Capital Medical University, National Clinical Research Center for Cardiovascular Diseases Beijing China.
Heart Health Research Center Beijing China.
J Am Heart Assoc. 2023 Aug 15;12(16):e029623. doi: 10.1161/JAHA.123.029623. Epub 2023 Aug 7.
Background The knowledge gap regarding whether the correlation between atrial fibrillation (AF) and dementia in observational studies is causation or driven by other shared risk factors remains substantially unfilled. Methods and Results We performed a comprehensive 2-sample Mendelian randomization study to evaluate the causal effect of AF on overall dementia and its subtypes, including vascular dementia, Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. The primary results in inverse variance-weighted analyses were further validated by various Mendelian randomization sensitivity analyses. Additionally, we conducted multivariable Mendelian randomization to examine 10 candidate mediators of the causal association of AF and dementia. Genetic predisposition to AF was modestly associated with an increased risk of overall dementia (odds ratio, 1.140 [95% CI, 1.023-1.271]; =0.018) and strongly associated with vascular dementia (odds ratio, 1.350 [95% CI, 1.076-1.695]; =0.010). Genetically predicted AF indicated neutral effects on Alzheimer dementia, Lewy body dementia, and frontotemporal dementia. In multivariable Mendelian randomization analysis, the total effect of AF on overall dementia was remarkably attenuated by adjusting for genetic effect for ischemic stroke (odds ratio, 1.068 [95% CI, 0.953-1.197]; =0.259) and low cardiac output (odds ratio, 1.046 [95% CI, 0.926-1.181]; =0.475), indicating that the causal association of genetically predicted AF with dementia was potentially mediated by ischemic stroke and low cardiac output. The causal effect of genetically predicted AF on dementia was independent of cerebral small-vessel disease and brain volume phenotypes. Conclusions Our findings provided novel evidence supporting the causal effect of genetically predicted AF on dementia mediated by ischemic stroke and low cardiac output. Future clinical trials are warranted to evaluate the potential role of appropriate AF management in dementia prevention.
在观察性研究中，关于心房颤动（AF）与痴呆之间的相关性是因果关系还是由其他共同的危险因素驱动，这一知识空白仍然很大。
我们进行了一项全面的两样本孟德尔随机化研究，以评估 AF 对总体痴呆及其亚型（包括血管性痴呆、阿尔茨海默病痴呆、路易体痴呆和额颞叶痴呆）的因果效应。逆方差加权分析中的主要结果通过各种孟德尔随机化敏感性分析进一步验证。此外，我们进行了多变量孟德尔随机化分析，以检验 AF 和痴呆因果关联的 10 个候选中介因素。AF 的遗传易感性与总体痴呆风险增加适度相关（优势比，1.140 [95%置信区间，1.023-1.271]；=0.018），与血管性痴呆强烈相关（优势比，1.350 [95%置信区间，1.076-1.695]；=0.010）。遗传预测的 AF 对阿尔茨海默病痴呆、路易体痴呆和额颞叶痴呆无影响。在多变量孟德尔随机化分析中，通过调整缺血性卒中（优势比，1.068 [95%置信区间，0.953-1.197]；=0.259）和低心输出量（优势比，1.046 [95%置信区间，0.926-1.181]；=0.475）的遗传效应，AF 对总体痴呆的总效应明显减弱，表明遗传预测的 AF 与痴呆之间的因果关系可能由缺血性卒中和低心输出量介导。遗传预测的 AF 对痴呆的因果效应独立于脑小血管疾病和脑容量表型。
我们的研究结果提供了新的证据，支持遗传预测的 AF 通过缺血性卒中和低心输出量对痴呆的因果作用。未来需要进行临床试验，以评估适当的 AF 管理在预防痴呆方面的潜在作用。
