Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies.
Which Risk Factors Causally Influence Dementia? A Systematic Review of Mendelian Randomization Studies.
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DOI：
10.3233/jad-180013
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Llewellyn DJ
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文献类型：
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作者：
Kuźma E;Hannon E;Zhou A;Lourida I;Bethel A;Levine DA;Lunnon K;Thompson-Coon J;Hyppönen E;Llewellyn DJ
痴呆症的许多风险因素已经得到了很好的确定，尽管这些关联的因果性质仍然不清楚。系统回顾孟德尔随机化（MR）研究，探讨风险因素与整体认知功能或痴呆之间的因果关系。我们检索了从成立到2017年2月的五个数据库，并进行了引文检索，包括调查任何风险因素与全球认知功能，全因痴呆或痴呆亚型之间关系的MR研究。两名评审员独立评估标题和摘要、全文和研究质量。我们纳入了18项MR研究，调查教育、生活方式因素、心血管因素和相关生物标志物、糖尿病相关因素和其他内分泌因素以及端粒长度。研究的质量主要是好的，但有8项研究的样本量和统计功效评分较低。最令人信服的因果证据是发现较短的端粒与阿尔茨海默病（AD）风险增加有关。吸烟量、维生素D、同型半胱氨酸、收缩压、空腹血糖、胰岛素敏感性和高密度脂蛋白胆固醇的因果关系证据较弱。对于大多数暴露，并不存在重复性良好的相关性，我们不能完全忽视生存率和诊断偏倚，或多效性效应的可能性。遗传学证据支持端粒长度和AD之间的因果关系，而其他危险因素的有限证据在很大程度上是不确定的，吸烟量，维生素D，同型半胱氨酸和选定的代谢标志物的初步证据。其他风险因素缺乏更有力的证据可能反映了统计功效不足。因此，更大规模的精心设计的MR研究将有助于确定这些痴呆风险因素的因果关系。
Numerous risk factors for dementia are well established, though the causal nature of these associations remains unclear. To systematically review Mendelian randomization (MR) studies investigating causal relationships between risk factors and global cognitive function or dementia. We searched five databases from inception to February 2017 and conducted citation searches including MR studies investigating the association between any risk factor and global cognitive function, all-cause dementia or dementia subtypes. Two reviewers independently assessed titles and abstracts, full-texts, and study quality. We included 18 MR studies investigating education, lifestyle factors, cardiovascular factors and related biomarkers, diabetes related and other endocrine factors, and telomere length. Studies were of predominantly good quality, however eight received low ratings for sample size and statistical power. The most convincing causal evidence was found for an association of shorter telomeres with increased risk of Alzheimer’s disease (AD). Causal evidence was weaker for smoking quantity, vitamin D, homocysteine, systolic blood pressure, fasting glucose, insulin sensitivity, and high-density lipoprotein cholesterol. Well-replicated associations were not present for most exposures and we cannot fully discount survival and diagnostic bias, or the potential for pleiotropic effects. Genetic evidence supported a causal association between telomere length and AD, whereas limited evidence for other risk factors was largely inconclusive with tentative evidence for smoking quantity, vitamin D, homocysteine, and selected metabolic markers. The lack of stronger evidence for other risk factors may reflect insufficient statistical power. Larger well-designed MR studies would therefore help establish the causal status of these dementia risk factors.