Reta Lilla Research Laboratories, Department of Molecular Neuroscience, University College London Institute of Neurology and UK Dementia Research Institute, University College London, London, UK.
Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences and Dementia Research Institute, Cardiff University, Cardiff, UK.
Hum Mol Genet. 2019 Nov 21;28(R2):R235-R240. doi: 10.1093/hmg/ddz163.
The failure of recent clinical trials in Alzheimer's disease has highlighted the need for the development of a more complete understanding of the pathogenesis of the disorder and also a belief that therapies may only work if given very early in the disease process before overt symptoms occur. The rare, early onset forms of the disease are all caused by mutations which make amyloid deposition a more likely event. Here we discuss the recent data showing that, in contrast, much of the risk of late onset disease is encoded by loci involved in lipid metabolism and/or encoded by microglia. We discuss these finding and suggest that amyloid induced membrane damage may be a key factor in disease and also review the evidence that genome wide genetic analysis can substantially help in the prediction of those individuals at high risk of disease in the general population.
最近在阿尔茨海默病临床试验中的失败突显了对该疾病发病机制有更全面了解的必要性，同时也认为治疗方法只有在明显症状出现之前在疾病过程的早期给予才可能有效。该疾病罕见的早发形式都是由导致淀粉样蛋白沉积可能性增加的突变引起的。在这里，我们讨论了最近的数据，表明与早发形式相反，发病晚的大部分风险是由涉及脂质代谢的基因座或由小胶质细胞编码的基因座决定的。我们讨论了这些发现，并认为淀粉样蛋白诱导的膜损伤可能是疾病的一个关键因素，还回顾了全基因组遗传分析可以极大地帮助预测一般人群中患该病风险高的个体的证据。
