Division of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK.
UK Dementia Research Institute, School of Medicine, Cardiff University, Cardiff, UK.
Nat Neurosci. 2020 Mar;23(3):311-322. doi: 10.1038/s41593-020-0599-5. Epub 2020 Feb 28.
Genes play a strong role in Alzheimer's disease (AD), with late-onset AD showing heritability of 58-79% and early-onset AD showing over 90%. Genetic association provides a robust platform to build our understanding of the etiology of this complex disease. Over 50 loci are now implicated for AD, suggesting that AD is a disease of multiple components, as supported by pathway analyses (immunity, endocytosis, cholesterol transport, ubiquitination, amyloid-β and tau processing). Over 50% of late-onset AD heritability has been captured, allowing researchers to calculate the accumulation of AD genetic risk through polygenic risk scores. A polygenic risk score predicts disease with up to 90% accuracy and is an exciting tool in our research armory that could allow selection of those with high polygenic risk scores for clinical trials and precision medicine. It could also allow cellular modelling of the combined risk. Here we propose the multiplex model as a new perspective from which to understand AD. The multiplex model reflects the combination of some, or all, of these model components (genetic and environmental), in a tissue-specific manner, to trigger or sustain a disease cascade, which ultimately results in the cell and synaptic loss observed in AD.
基因在阿尔茨海默病（AD）中起着重要作用，迟发性 AD 的遗传率为 58-79%，早发性 AD 的遗传率超过 90%。遗传关联为我们深入了解这种复杂疾病的病因提供了一个强大的平台。现在已经有 50 多个基因座与 AD 相关，这表明 AD 是一种多成分的疾病，这一观点得到了通路分析（免疫、内吞作用、胆固醇转运、泛素化、淀粉样蛋白-β 和 tau 处理）的支持。超过 50%的迟发性 AD 遗传率已经被捕获，这使得研究人员能够通过多基因风险评分计算 AD 遗传风险的积累。多基因风险评分的疾病预测准确率高达 90%，这是我们研究武器库中的一个令人兴奋的工具，它可以让我们选择那些具有高多基因风险评分的人进行临床试验和精准医学。它还可以允许对组合风险进行细胞建模。在这里，我们提出了多重模型，作为一种新的视角来理解 AD。多重模型以组织特异性的方式反映了某些或所有这些模型成分（遗传和环境）的组合，以引发或维持疾病级联反应，最终导致 AD 中观察到的细胞和突触丢失。
