Development of Blood-based Circular RNA Biomarkers for Alzheimer's Disease

项目总结-第一阶段应用的目标是PAS-19-316，以解决以下优先事项：a）新的、成本- 有效的，微创的生物标志物，可用于筛选和B）研究，将确定新的 可以作为阿尔茨海默病和相关疾病进展的替代指标的生物标志物 痴呆（AD/ADRD）。具体来说，Vivid Genomics正在探索循环RNA（circRNA）在血液中的应用。 作为AD和AD进展的生物标志物，包括可能识别症状前AD。的 AD的巨大公共卫生挑战由于缺乏可获得的非侵入性工具而变得复杂， 在死前确诊了这种疾病尽管脑脊液中的成像和AD生物标志物 (CSF)虽然它们可以提供对疾病状态的洞察，但它们不是常规筛查的理想选择。最近报告的血液- 基于淀粉样蛋白B和磷酸化tau（p-tau）的筛选代表了一个重大进展，但它们需要 这些方法不容易扩展或在早期疾病中可能不具有足够的灵敏度。此外他们 在特定时间点评估淀粉样蛋白B和p-tau的存在，目前不能用于指示 疾病进展的速度或未来下降的可能性。因此，开发新的可扩展的，具有成本效益的， 微创血液生物标志物可以为高风险患者的常规筛查提供急需的工具。 个体，常规随访以跟踪AD进展，或持续监测以评估治疗功效。最近 研究结果表明，在患有和不患有AD的患者的大脑中， 与AD诊断、临床严重程度和神经病理学严重程度显著相关。此外，变化 甚至在症状前患者中也可以检测到in circRNA表达。初步研究表明， 标记物在血液中也有差异表达，为探索基于血液的circRNA提供了基础， AD和/或AD进展的生物标志物。在此概念验证阶段I SBIR中，Vivid建议确定 多种circRNA，其在血液中的表达与AD诊断、临床严重程度和/或神经系统疾病相关。 病理严重性。瞄准识别与AD状态和AD相关的血液circRNA- 生物标志物阳性。RNA-seq将用于分析骑士医院300名患者血液中的circRNA。 阿尔茨海默病研究中心队列。将基于以下内容开发感兴趣的circRNA的等级排序列表： 根据其与AD性状的关联强度，调整了中值转录完整性评分，发病年龄， 批次、性别和遗传祖先。然后将在来自300名患者的血液中验证关联和等级顺序 AD Neuroimaging Initiative（ADNI）的研究。通过/不通过标准：鉴别≥ 2种血液circRNA 与一个或多个AD性状相关（FDR < 0.05）。影响-概念验证将为 开发基于血液的circRNA作为AD和/或AD进展的生物标志物。验证和监管 清除将为目前的生物标志物提供一种可扩展的、具有成本效益的、微创的替代方法， 可以支持高风险个体的常规筛查，并为治疗决策和临床试验设计提供信息。

PROJECT SUMMARY—This Phase I application targets PAS-19-316 to address the priorities for a) new, cost- effective, minimally-invasive biomarkers that could be used for screening and b) research that would identify new biomarkers that could serve as surrogate measures for disease progression in Alzheimer’s Disease and Related Dementias (AD/ADRD). Specifically, Vivid Genomics is exploring the use of circular RNAs (circRNAs) in blood as a biomarker of AD and AD progression, including the possible identification of presymptomatic AD. The enormous public health challenge of AD is complicated by the lack of accessible, non-invasive tools for definitively diagnosing the disease prior to death. Although imaging and AD biomarkers in cerebrospinal fluid (CSF) can provide insight into disease status, they are not ideal for routine screening. Recently reported blood- based screens for amyloid b and phosphorylated tau (p-tau) represent a significant advance, but they require methods that are not easily scalable or may not have adequate sensitivity in early disease. In addition, they assess the presence of amyloid b and p-tau at a particular point in time and cannot currently be used to indicate the rate of disease progression or future likelihood of decline. Thus, developing new scalable, cost-effective, minimally-invasive blood-based biomarkers could provide a much-needed tool for routine screening in high-risk individuals, routine follow-up to track AD progression, or ongoing monitoring to assess treatment efficacy. Recent findings indicate several circRNAs differentially expressed in the brains of patients with and without AD are significantly associated with AD diagnosis, clinical severity, and neuropathological severity. In addition, changes in circRNA expression can be detected even in presymptomatic patients. Preliminary studies indicate these markers are also differentially expressed in blood, providing a basis for exploring blood-based circRNAs as biomarkers of AD and/or AD progression. In this proof-of-concept Phase I SBIR, Vivid proposes to identify multiple circRNAs whose expression in blood is associated with AD diagnosis, clinical severity, and/or neuro- pathological severity. Aim. Identify blood-based circRNAs that are associated with AD status and AD- biomarker positivity. RNA-seq will be used to analyze circRNAs in blood from 300 patients in the Knight Alzheimer's Disease Research Center cohort. A rank-ordered list of circRNAs of interest will be developed based on the strength of their association with AD traits adjusted for median transcript integrity score, age of onset, batch, sex, and genetic ancestry. Associations and rank order will then be validated in blood from 300 patients in the AD Neuroimaging Initiative (ADNI) cohort. Go/No-Go Criterion: Identify ≥ 2 blood-based circRNAs correlated with one or more AD traits (FDR < 0.05). Impact—Proof-of-concept would provide a foundation for development of blood-based circRNAs as biomarkers of AD and/or AD progression. Validation and regulatory clearance would provide a scalable, cost-effective, minimally-invasive alternative to current biomarkers, which could support routine screening of high-risk individuals and inform treatment decisions and clinical trial designs.