Project 3: Biomarkers for DS Clinical Trials

项目3摘要 几乎所有患有唐氏综合症（DS）的成年人，如果他们活到20岁，都将面临阿尔茨海默病（AD）的负担。 足够的高龄。尽管在针对AD的临床试验上花费了数十亿美元， 然而，在成年DS患者中，仍然缺乏针对这种毁灭性疾病的试验。阿尔茨海默 生物标志物联盟-唐氏综合征（ABC-DS）提供了一个独特的机会，以产生生物标志物， 推进基于精准医学的临床试验，靶向DS中的AD（DS-AD）。此外，NIH还包括 该项目明确为针对这一人群的新型疗法奠定了基础。项目1将检查AT（N） 在DS框架中，项目2将确定与MCI-DS和DS-AD相关的基因组标记，项目3将 将所有这些工作转化为一种新的精确医学模型，直接解决里程碑1.A 在NIA AD & ADRD Milestones的“人口研究，精准医学和健康差异”下。 ABC-DS队列接受详细的纵向评估，包括医学和神经心理学评估。 评估、成像（MRI、PET）和液体（CSF和血液“组学”）生物标志物，如核心中所述。当 在可能的情况下，神经病理学核心将获取脑组织和神经病理学数据。目前的团队已经 丰富的经验，推进新的“组学”生物标志物的神经退行性疾病。在我们之前的工作中，我们 已经产生了基于血液的生物标志物，这些生物标志物在（1）检测DS-AD和MCI-DS以及 (2)预测DS成年患者未来发生MCI和AD的风险。在我们的工作中， 在一般人群中，我们已经确定了患者的亚组，并表明这些亚组的差异 对靶向治疗有反应。我们的初步数据还表明，亚组存在于成年DS。 在这里，我们将利用ABC-DS队列来解决以下具体目标：目标1： 用于临床试验富集的诊断生物标志物，用于延迟和减缓DS成人中的AD（COU 1： 诊断生物标志物）;目的2：用于延迟和 减缓DS成人的AD（COU 2：预测生物标志物）;目标3：产生替代生物标志物结果 用于延迟和减缓DS成人AD的临床试验（COU 3：反应生物标志物）;目标4：翻译 将项目1和2的研究结果转化为DS中AD的精准医学模型。预计调查结果 来自项目1和2的生物标志物将告知上述生物标志物，因此，生物标志物和生物标志物概况 项目1和项目2中确定的技术将在项目3的框架内进行测试。项目3意义重大， 它将（1）显著推进治疗和延迟DS中AD的精确医学方法，以及（2） 为AD的精准医学模型的创建和实施提供了一个模型 人口

PROJECT 3 ABSTRACT Nearly all adults with Down syndrome (DS) will face the burden of Alzheimer's disease (AD) if they live to sufficient advanced age. Despite the billions of dollars expended on clinical trials targeting AD in the general population, there remains a dearth of trials targeting this devastating disease in adults with DS. The Alzheimer's Biomarker Consortium – Down Syndrome (ABC-DS) offers a unique opportunity to generate biomarkers to advance precision medicine based clinical trials targeting AD in in DS (DS-AD). Furthermore, the NIH INCLUDE Project explicitly sets the stage for novel therapies targeting this population. Project 1 will examine an AT(N) framework in DS, Project 2 will identify genomic markers associated with MCI-DS and DS-AD and Project 3 will translate all of this work into a novel precision medicine model to DS-AD, directly addressing Milestone 1.A under “Population Studies, Precision Medicine & Health Disparities” of the NIA AD & ADRD Milestones. The ABC-DS cohort undergoes detailed longitudinal assessments including medical and neuropsychological assessments, imaging (MRI, PET) and fluid (CSF and blood “omics”) biomarkers as outlined in the Cores. When possible, the Neuropathology Core will acquire brain tissues and neuropathology data. The current team has extensive experience advancing novel “omics” biomarkers for neurodegenerative diseases. In our prior work, we have generated blood-based biomarkers that are highly accurate in (1) detecting DS-AD and MCI-DS as well as (2) predicting future risk for the development of MCI and AD among adults with DS. In our work in AD in the general population, we have identified subgroups of patients and shown that these subgroups differentially respond to targeted therapeutics. Our preliminary data also show that subgroups exist among adults with DS. Here we will leverage the ABC-DS cohort to address the following Specific Aims: Aim 1: Generation of Diagnostic Biomarkers for Clinical Trial Enrichment for Delaying and Slowing AD in Adults with DS (COU 1: Diagnostic Biomarker); Aim 2: Characterization of Predictive Biomarkers for Clinical Trials for Delaying and Slowing AD in Adults with DS (COU 2: Predictive Biomarker); Aim 3: Generate Surrogate Biomarker Outcomes for Clinical Trials for Delaying and Slowing AD in Adults with DS (COU 3: Response Biomarker); Aim 4: Translate findings from Projects 1 and 2 into a precision medicine model for AD in DS. It is anticipated that findings from Projects 1 and 2 will inform the biomarkers above and, therefore, biomarkers and biomarker profiles identified in Projects 1 and 2 will be tested within the framework of Project 3. Project 3 is highly significant as it will (1) significantly advance a precision medicine approach to treating and delaying AD in DS as well as (2) provide a model for the creation and implementation of a precision medicine model for AD in the general population.