Early identification of Alzheimer's disease: dynamic biomarkers for enrichment of trials

阿尔茨海默病（AD）是一种致命的疾病，仅在英国就直接影响了82万人，给英国经济造成230亿英镑的损失，超过了癌症和心脏病的总和。目前对阿尔茨海默病（AD）的所有治疗方法都只能缓解症状，尽管许多人试图找到治愈方法。最近的研究表明，大脑扫描可以在临床诊断前20年发现阿尔茨海默病的早期迹象。研究人员现在正竞相开发能够延缓阿尔茨海默病发病的药物，因为他们相信延缓而不是逆转疾病的进程更容易。开发这种治疗方法的主要障碍是昂贵的脑部扫描，这是识别早期阿尔茨海默症患者所必需的。这项研究将开发一种相对便宜的替代方法，使识别大量有阿尔茨海默病早期症状的人成为可能，并在这些人身上测试延缓阿尔茨海默病发病的药物。在研究项目中，Steven Kiddle博士将需要应用和开发统计方法来整合来自脑部扫描、遗传学、功能基因组学和认知测试的复杂数据。他将得到来自剑桥大学的生物统计学专家Chris Wallace博士的指导，并将与临床训练有素的研究人员Simon Lovestone教授和Claire steve博士合作。Steven Kiddle博士和其他人过去的研究已经确定了可以在血液测试中测量的血液蛋白质，这可以识别阿尔茨海默病的早期迹象，作为昂贵的脑部扫描的替代方法。然而，这些早期发现在用于临床之前还需要进一步的验证。在这项研究中，Kiddle博士将研究这些血液蛋白的潜力，以及遗传学和认知测试的得分，以识别有阿尔茨海默病早期症状的受试者。这项工作将从对双胞胎的研究开始，以确定哪些血液蛋白水平受到他们目前健康状况的影响，并控制遗传因素。这将包括一项对同卵双胞胎进行血液测试和脑部扫描的研究，看看拟议的血液测试是否能揭示基因相同的个体在阿尔茨海默病早期症状上的差异。进一步的工作将尝试通过调整现有的认知能力评估，利用认知测试来识别阿尔茨海默病的早期迹象。认知测试包括一系列单独的任务，测试记忆和认知的不同方面。已知现有认知测试的总分对晚期AD敏感，但被认为对早期AD不太敏感。然而，单独的任务，或者巧妙的任务组合，还没有被评估出在阿尔茨海默病早期阶段识别人的能力。此外，基因、认知和血液标记的结合可能比单独使用每种标记更准确地识别受试者。血液标志物要想在大脑中反映出AD的迹象，就必须通过血脑屏障。为了调查这个问题，我将研究生前被诊断患有阿尔茨海默病的人的死后大脑，以及同等数量的未被诊断患有阿尔茨海默病的人的死后大脑。将进行综合分析，将神经病理学、遗传学和多个基因组水平的数据联系起来，例如：表观遗传学（调节基因表达）、基因表达和蛋白质水平。Kiddle博士将与剑桥大学的Chris Wallace博士合作，进一步开发适合这种方法的统计方法。最后，Kiddle博士将使用统计模型来研究阿尔茨海默病早期症状与最佳基因、血液蛋白和认知标志物之间的因果关系。这种新方法将揭示哪些血液蛋白和认知标志物动态地反映了阿尔茨海默病的早期迹象，因此将揭示哪些标志物应该在未来进行研究。将寻求资金进行大规模研究，以评估这些标记物的效用。

Alzheimer's disease (AD) is a fatal disease which in the UK alone directly affects 820,000 people, costing the UK economy £23 billion pounds, more than cancer and heart disease combined. All current treatments for Alzheimer's disease (AD) only provide relief from symptoms, despite many attempts to develop a cure. Recent research has shown that brain scans can be used to spot early signs of AD, up to 20 years before a clinical diagnosis. Researchers are now racing to develop drugs that can delay the onset of AD, based on the belief that it will be easier to delay rather than reverse the disease process. The major barrier in the development of such a treatment is the expensive brain scans necessary to identify people with early signs of AD. This fellowship will develop a relatively inexpensive alternative to make it practical to identify large numbers of people with the early signs of AD, in whom drugs to delay AD onset will be tested.Within the fellowship Dr. Steven Kiddle will need to apply and develop statistical approaches to integrate complex data from brain scans, genetics, functional genomics and cognitive tests. He will be mentored by an expert in biostatistics, Dr. Chris Wallace from Cambridge University, and will collaborate with clinically trained researchers Professor Simon Lovestone and Dr. Claire Steves. Past research by Dr. Steven Kiddle and others have identified blood proteins which could be measured in a blood test, this could identify early signs of AD as an alternative to expensive brain scans. However, these early findings need much further validation before being used in the clinic. During this fellowship Dr. Kiddle will examine the potential of these blood proteins, as well as genetics and scores from cognitive tests, to identify subjects with early signs of AD.This work will begin with a study in twins to determine which blood protein levels are affected by their current health, controlling for genetics. This will include a study that uses both blood tests and brain scans in identical twins, to see if the proposed blood test can reveal differences in early signs of AD in genetically identical individuals. Further work will attempt to identify early signs of AD using cognitive tests, by adapting existing assessments of cognitive abilities. Cognitive tests consist of a set of individual tasks which test different aspects of memory and cognition. Total scores for existing cognitive tests are known to be sensitive to late AD, but are thought to be less sensitive to early stage AD. However, individual tasks, or a clever combination of tasks, have not yet been assessed for ability to identify people in the early stages of AD. In addition, the combination of genetic, cognitive and blood markers may allow subjects to be identified with greater accuracy than each marker alone.For blood markers to reflect signs of AD in the brain they must pass the blood-brain barrier. To investigate this I will study post-mortem brains from people who had been diagnosed with AD in life, and an equal number of people who had not recieved an AD diagnosis. Integrative analysis will be performed to link data on neuropathology, genetics, and multiple genomic levels, such as: epigenetics (which regulates gene expression), gene expression and protein levels. Dr. Kiddle will collaborate with Dr. Chris Wallace at Cambridge University to further develop statistical approaches tailored to this approach.Finally, Dr. Kiddle will use statistical models to study causal relationships between early signs of AD and the best genetic, blood protein and cognitive markers. This novel approach will reveal which blood protein and cognitive markers dynamically reflect the early signs of AD, and therefore will reveal which markers should be studied in the future. Funding will be sought to setup large-scale studies to assess the utility of these markers.