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到82万人，给英国经济造成的损失达230亿英镑，超过了癌症和心脏病的总和。目前所有治疗阿尔茨海默病(AD)的方法都只能缓解症状，尽管许多人试图开发一种治疗方法。最近的研究表明，脑部扫描可以用来发现阿尔茨海默病的早期迹象，最长可在临床诊断前20年。研究人员现在正在争先恐后地开发可以推迟AD发病的药物，因为他们相信，推迟而不是逆转疾病过程会更容易。开发这种治疗方法的主要障碍是昂贵的脑部扫描，这是识别有早期AD症状的人所必需的。该奖学金将开发一种相对便宜的替代方案，使识别大量具有AD早期症状的人变得可行，在这些人中，将测试延缓AD发病的药物。在该奖学金中，史蒂文·基德尔博士将需要应用和开发统计方法，以整合来自脑扫描、遗传学、功能基因组学和认知测试的复杂数据。他将得到生物统计学专家、剑桥大学的克里斯·华莱士博士的指导，并将与经过临床培训的研究人员西蒙·洛夫斯通教授和克莱尔·史蒂夫斯博士合作。史蒂文·基德尔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，这可以确定AD的早期迹象，作为昂贵的脑部扫描的替代方案。然而，这些早期的发现在应用于临床之前还需要进一步的验证。在这项研究中，基德尔博士将检查这些血液蛋白的潜力，以及遗传学和认知测试的分数，以确定有早期AD迹象的受试者。这项工作将从一项针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，并控制遗传学。这将包括一项对同卵双胞胎进行血液测试和脑扫描的研究，以确定拟议的血液测试是否可以揭示基因相同的人患阿尔茨海默病的早期迹象的差异。进一步的工作将尝试通过调整现有的认知能力评估，使用认知测试来识别AD的早期迹象。认知测试由一系列测试记忆和认知不同方面的单独任务组成。众所周知，现有认知测试的总分对晚期AD敏感，但被认为对早期AD不那么敏感。然而，单独的任务或任务的巧妙组合还没有被评估在AD的早期阶段识别人的能力。此外，基因、认知和血液标记物的结合可能会使受试者比单独使用每个标记物更准确。血液标记物要想反映大脑中的阿尔茨海默病迹象，必须通过血脑屏障。为了研究这一点，我将研究生前被诊断患有阿尔茨海默病的人和同样数量的未接受阿尔茨海默病诊断的人的死后大脑。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。基德尔博士将与剑桥大学的克里斯·华莱士博士合作，进一步开发针对这一方法量身定做的统计学方法。最后，基德尔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遗传、血液蛋白质和认知标记之间的因果关系。这一新的方法将揭示哪些血液蛋白和认知标志物动态反映AD的早期迹象，因此将揭示哪些标志物应该在未来进行研究。将寻求资金来建立大规模研究，以评估这些标记的效用。

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.