Background Dementia incidence is increasing across the globe and currently there are no disease-modifying pharmaceutical treatments. The Lancet Commission on dementia identified 12 modifiable risk factors which explain 40% of dementia incidence. However, whether these associations are causal in nature is unclear. Objective To examine the modifiable risk factors for dementia as identified in the Lancet Commission review using Mendelian randomisation (MR) to establish if, based on genetic evidence, these associations with different dementia subtypes are causal in nature. Methods Publicly available genome-wide association study data were used for 10 risk factors and Alzheimer’s disease (AD), frontotemporal dementia and dementia with Lewy bodies. Two-sample MR using the inverse varianceweighted method was conducted to test for causal relationships. Weighted median MR and MR-Egger were used to test for pleiotropic effects. Results Genetic proxied risk for higher levels of smoking (OR: 0.80 (95% CI: 0.69; 0.92), p=0.002), obesity (OR: 0.87 (95% CI: 0.82; 0.92), p<0.001) and blood pressure (OR: 0.90 (95% CI: 0.82; 0.99), p=0.035) appeared to be protective against the risk of AD. Post hoc analyses indicated these associations had pleiotropic effects with the risk of coronary artery disease. Genetic proxied risk of educational attainment was found to be inconsistently associated with the risk of AD. Conclusions and implications Post hoc analysis indicated that the apparent protective effects of smoking, obesity and blood pressure were a result of survivor bias. The findings from this study did not support those presented by the Lancet Commission. Evidence from causal inference studies should be considered alongside evidence from epidemiological studies and incorporated into reviews of the literature. Data are available in a public, open access repository.

中文翻译：

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使用孟德尔随机化检查柳叶刀委员会痴呆症的风险因素

背景 痴呆症发病率在全球范围内不断增加，目前尚无缓解疾病的药物治疗方法。《柳叶刀》痴呆症委员会确定了 12 个可改变的危险因素，解释了 40% 的痴呆症发病率。然而，这些关联本质上是否具有因果关系尚不清楚。目的 使用孟德尔随机化 (MR) 检查柳叶刀委员会审查中确定的可改变的痴呆风险因素，以根据遗传证据确定这些与不同痴呆亚型的关联本质上是否存在因果关系。方法 使用公开的全基因组关联研究数据，研究 10 种危险因素以及阿尔茨海默病 (AD)、额颞叶痴呆和路易体痴呆。使用逆方差加权方法进行两样本 MR 来检验因果关系。加权中值 MR 和 MR-Egger 用于测试多效性效应。结果 较高水平吸烟（OR：0.80（95% CI：0.69；0.92），p=0.002）、肥胖（OR：0.87（95% CI：0.82；0.92），p<0.001）和血压的遗传代理风险（OR：0.90（95% CI：0.82；0.99），p=0.035）似乎可以预防 AD 风险。事后分析表明这些关联与冠状动脉疾病的风险具有多效性。研究发现，遗传代理的受教育程度风险与 AD 风险的相关性不一致。结论和意义事后分析表明，吸烟、肥胖和血压的明显保护作用是幸存者偏差的结果。这项研究的结果并不支持柳叶刀委员会提出的结果。因果推理研究的证据应与流行病学研究的证据一起考虑，并纳入文献综述。数据可在公共、开放访问存储库中获取。