Project 3: Biomarkers for DS Clinical Trials

项目3摘要 几乎所有患有唐氏综合症(DS)的成年人都将面临阿尔茨海默病(AD)的负担，如果他们活到 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 在人群中，针对患有DS的成年人的这种毁灭性疾病的试验仍然很少。阿尔茨海默氏症 生物标记物联合体-唐氏综合征(ABC-DS)为产生生物标记物提供了一个独特的机会 在DS(DS-AD)中以精确医学为基础的针对AD的临床试验进展。此外，国家卫生研究院还包括 该项目明确地为针对这一人群的新疗法奠定了基础。项目1将检查AT(N) DS中的框架，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DS-AD的新的精确医学模型，直接针对里程碑1.A 在NIA AD和ADRD里程碑的“人口研究、精确医学和健康差异”项下。 ABC-DS队列接受了详细的纵向评估，包括医学和神经心理学 评估、成像(核磁共振、正电子发射计算机断层扫描)和体液(脑脊液和血液“组学”)生物标志物，如岩心中概述的。什么时候 有可能，神经病理学核心将获得脑组织和神经病理学数据。目前的团队已经 发展神经退行性疾病的新型“组学”生物标记物的丰富经验。在我们之前的工作中，我们 产生了基于血液的生物标志物，在以下方面高度准确：(1)检测DS-AD和MCI-DS以及 (2)预测成人DS患者发生MCI和AD的未来风险。在我们在公元前的工作中 在普通人群中，我们已经确定了患者的亚组，并表明这些亚组有不同 对靶向治疗有反应。我们的初步数据还显示，患有DS的成年人中存在亚群。 在这里，我们将利用ABC-DS队列来解决以下具体目标：目标1：生成 临床试验浓缩用于延缓成人DS患者AD的诊断生物标记物(COU1： 诊断生物标记物)；目标2：临床试验的预测生物标记物的特征 延缓患有DS的成人阿尔茨海默病(COU2：预测性生物标记物)；目标3：产生替代生物标记物结果 用于延迟和减缓患有DS的成人AD的临床试验(CUU 3：反应生物标记物)；目标4：翻译 将项目1和项目2的结果转化为DS中AD的精确医学模型。预计调查结果 项目1和2将通知上面的生物标志物，因此，生物标志物和生物标志物概况 项目1和2中确定的项目将在项目3的框架内进行测试。项目3具有重要意义，因为 它将(1)显著推进治疗和延缓DS患者阿尔茨海默病的精确医学方法，以及(2) 为AD精准医学模型的建立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.