The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review.
The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review.
复制标题
DOI：
10.3389/fmed.2018.00108
复制
发表时间：
2018
影响因子：
3.9
通讯作者：
Davies P
中科院分区：
文献类型：
--
作者：
Freudenberg-Hua Y;Li W;Davies P
阿尔茨海默病（AD）是最常见的痴呆类型，其具有大量的遗传成分。AD主要影响老年人。因此，随着人口老龄化，痴呆症的患病率一直在上升。到目前为止，还没有有效的干预措施可以治愈或阻止AD的进展。唯一可用的治疗方法是管理痴呆症的某些症状和后果。目前最先进的AD医疗保健包括三个简单的原则：预防可预防的疾病，实现早期诊断，以及管理可管理的症状。本文综述了AD的危险因素、生物学诊断检测和治疗前景的现状。特别强调了AD遗传学的最新进展以及基因组数据可能支持预防，早期干预和开发有效的药物治疗的方式。APP、PSEN1和PSEN2基因突变导致遵循孟德尔遗传模式的早发性阿尔茨海默病（EOAD）。对于晚发性阿尔茨海默病（LOAD），APOE 4在二十多年前被确定为主要风险等位基因。基于人群的晚发性AD全基因组关联研究现已在大约30个遗传基因座上发现了常见变异。此外，已经在几个基因中鉴定出影响LOAD风险的罕见变异（等位基因频率<1%）。这些遗传学上的进步拓宽了我们对AD生物学基础的认识。此外，已知的遗传风险变异可用于识别有AD风险的症状前个体，并支持有症状受试者的诊断评估。基因知识也可能促进精准医疗。精准医学的目标是利用生物学知识和其他健康信息来预测个体疾病风险，了解疾病病因，识别疾病亚类，改善诊断，并提供个性化治疗策略。我们讨论了遗传学在推进AD精准医学方面的潜在作用沿着伦理挑战。我们概述了将基因组学应用于转化临床研究的策略，这不仅可以提高痴呆症诊断的准确性，从而实现更个性化的治疗策略，而且还可以加快新药和干预措施的发现。
Alzheimer’s disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1, and PSEN2 genes cause early onset Alzheimer’s disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer’s disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions.