Screening ADNI patient cohorts to identify a sub-population that are AD early progressors in validating the prognostic ability of the Alzosure Predict blood test, 6 years in advance of current methods

摘要 AD是一种进行性痴呆，具有从正常认知到不可逆认知的疾病严重度梯度， 这是一种神经损伤，占所有痴呆症的60%到80%。每年有1000万新病例， 全球病例总数，包括2019年仅美国就有580万人患有AD。此外，委员会认为， 预计这些数字在未来十年或二十年将大幅上升。AD的社会经济负担是 2010年至2015年间，全球痴呆症相关费用增加了35%，到2030年， 预计将达到2万亿美元。目前，疾病管理是对症的（胆碱酯酶抑制剂或 NMDA拮抗剂）作为确定的治疗选择尚未确立。由于缺乏补救措施或 对于AD的治愈性治疗，改善临床结局的最佳选择是早期发现和预防， 使治疗尽早，最大限度地提高身体，精神和行为健康。目前的诊断方法 是耗时的，模糊的或不确定的，侵入性的，昂贵的，通常需要先进的认知 扫描测试或甚至需要检查脑脊液（CSF）的特定疾病生物标志物。 然而，有证据表明，AD的病理生理特征发生在最初症状出现之前几十年。 因此，迫切需要微创早期疾病检测。 p53蛋白在癌症等几种疾病中起着明确的作用，其失调也有助于 合并症如糖尿病、肥胖症和衰老相关的神经退行性疾病。具体来说，P53 在散发性AD患者的外周血成纤维细胞中观察到错误折叠/解折叠（U-p53），但在AD患者的外周血成纤维细胞中没有观察到。 年龄匹配的非AD受试者在AD发病机制中存在改变的p53是有据可查的 基于超过20年的研发，由Diadem开发，AlzoSure Predict是一种微创，成本 有效的，基于血液的测试能够检测U-p53 AZ。为了解决时间和成本效益早期诊断的差距 AD样品作为血浆、脑组织和CSF，来自由于以下原因而处于认知衰退的不同阶段的个体： AD进展并由ADNI的良好表征的回顾性和纵向队列招募1，2，3将 通过AlzoSure® Predict进行分析。来自同一生物样品的不同生物样品的可用性和分析 个体将提供关于生物标志物在大脑中展开过程的发生的额外知识 和/或系统水平。主要目标是鉴定早期进展个体的亚群， 纵向队列中的AD。这将通过一些研究目标来实现，特别是： 目的1，将验证生物标志物区分认知衰退的不同阶段的能力;具体而言， 目标2，还将允许建立与其他痴呆相比的生物标志物对AD的特异性; 具体目标3将通过将患者分类为以下类型来证实U-p53 AZ预后价值的临床实用性： 疾病分类和阶段;具体目标4将提供AlzoSure检测的性能与 目前AD的诊断和预后方法。

ABSTRACT AD is a progressive dementia with a disease-severity gradient from normal cognition to irreversible cognitive impairment, and accounts for 60 to 80% of all dementias. There are 10 million new cases per year, and 50 million total cases worldwide, including 5.8 million people in the United States alone living with AD in 2019. Furthermore, these figures are expected to significantly escalate in the next decade or two. The AD socioeconomic burden is substantial; worldwide dementia-related costs increased 35% between 2010 and 2015, and by 2030 are estimated to reach 2 trillion USD. At present, disease management is symptomatic (cholinesterase inhibitors or NMDA antagonists) as definitive care options have not yet been established. Given the lack of remedial or curative therapies for AD, the best option for improving clinical outcomes is early detection and prevention to enable treatment early-on, maximizing physical, mental, and behavioral wellbeing. Current methods of diagnosis are time consuming, ambiguous or inconclusive, invasive, and expensive, often requiring advanced cognitive scanning tests or even requiring examination of the cerebrospinal fluid (CSF) for specific disease biomarkers. However, evidence suggests AD pathophysiological features occur decades prior to initial symptomatic presentation, and as such, there is a crucial need for minimally-invasive early disease detection. The p53 protein plays a well-defined role several diseases as cancer, and its dysregulation also contributes to comorbidities such as diabetes, obesity, and aging-associated neurodegenerative disorders. Specifically, p53 misfolding/ unfolding (U-p53) was observed in sporadic AD subjects’ peripheral fibroblasts, but was not noted in age-matched non-AD subjects. The presence of altered p53 in AD pathogenesis is well documented Based on more than 20 years of R&D and developed by Diadem, AlzoSure Predict is a minimally invasive, cost effective, blood-based test able to detect U-p53AZ.To address the gap in time and cost-effective early diagnosis of AD samples as plasma, brain tissue and CSF from individuals at different stages of cognitive decline due to AD progression and recruited by the well characterized retrospective and longitudinal cohort of ADNI 1,2,3 will be analyzed by AlzoSure® Predict. The availability and the analysis of different biological samples from the same individuals will provide additional knowledge about occurrence of the biomarker unfolding process at the brain and/or systemic level. The main goal is the identification of the subpopulation of early progressing individuals to AD within the longitudinal cohorts. This will be accomplished in a number of study aims, particularly: Specific Aim 1, will validate the ability of the biomarker to discriminate the different stage of cognitive decline; Specific Aim 2, will also allow to establish the specificity of the biomarker toward AD compared to other dementias; Specific Aim 3 will confirm the clinical utility of the prognostic value of U-p53AZ by categorizing patients into disease classes and stages; Specific Aim 4 will provide a comparison of the performance of AlzoSure test against the current diagnostic and prognostic AD methods.