Kimel Family Translational Imaging-Genetics Laboratory, Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Cell Circuits Program, Broad Institute, Cambridge, MA, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Cell Circuits Program, Broad Institute, Cambridge, MA, USA; Center for Translational and Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Neurobiol Aging. 2018 Feb;62:243.e7-243.e14. doi: 10.1016/j.neurobiolaging.2017.09.033. Epub 2017 Oct 13.
Observational studies have consistently reported elevated plasma homocysteine as a risk factor for Alzheimer's disease (AD). However, results from clinical trials of homocysteine-lowering treatments are inconsistent. This discrepancy may be explained by a lack of causal association between homocysteine and AD. Mendelian randomization studies have the potential to provide insight into the causality of this association through studying the effect of genetic predisposition to high homocysteine on AD. Our analyses using summarized (n = 54,162) and individual participant (n = 6987) data from Caucasian participants did not show an effect of plasma homocysteine genetic risk on susceptibility to AD. Although with smaller sample sizes, further subanalyses also did not support an effect of genetically determined plasma homocysteine on cognitive impairment and decline, beta-amyloid and tau pathology and gray matter atrophy in AD. However, we found associations with tau tangle burden (n = 251) and gray matter atrophy (n = 605) in cognitively normal elderly. Our results do not support a causal association between elevated homocysteine and risk, severity, and progression of AD. However, the relationship between genetically determined homocysteine and brain pathology in cognitively normal elderly requires further exploration.
观察性研究一致报告血浆同型半胱氨酸升高是阿尔茨海默病 (AD) 的危险因素。然而，降低同型半胱氨酸治疗的临床试验结果并不一致。这种差异可能是由于同型半胱氨酸与 AD 之间缺乏因果关系。孟德尔随机化研究通过研究遗传易感性高同型半胱氨酸对 AD 的影响，有可能深入了解这种关联的因果关系。我们使用来自白种人参与者的汇总（n=54162）和个体参与者（n=6987）数据的分析并未显示血浆同型半胱氨酸遗传风险对 AD 易感性的影响。尽管样本量较小，但进一步的亚分析也不支持遗传决定的血浆同型半胱氨酸对认知障碍和认知能力下降、β-淀粉样蛋白和 tau 病理学以及 AD 中的灰质萎缩的影响。然而，我们发现同型半胱氨酸水平与 tau 缠结负担（n=251）和灰质萎缩（n=605）在认知正常的老年人中存在关联。我们的结果不支持血浆同型半胱氨酸升高与 AD 的风险、严重程度和进展之间存在因果关系。然而，在认知正常的老年人中，遗传决定的同型半胱氨酸与脑病理之间的关系需要进一步探索。
