Project 2: Biomarker Analysis, Non-Genetic Risk Factors, and Their Genetic Interactions

项目 2：生物标志物分析、非遗传风险因素及其遗传相互作用

基本信息

批准号：
10555697
负责人：
Jennifer S Yokoyama
金额：
$ 41.68万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555697
关键词：
Acculturation Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker American Amyloid beta-42 Amyloid beta-Protein Asia Asian Asian Americans Asian ancestry Asian population Biological Factors Biological Markers Blood Canada Clinical Clinical Trials Communities Creatine Dementia Development Diagnosis Diagnostic Diet Disease Education Environment Ethnic Population European European ancestry Future Genetic Genetic Risk Glial Fibrillary Acidic Protein Goals Immigration Impaired cognition Individual Intervention Intervention Trial Knowledge Leisure Activities Life Style Light Link Measures Mediating Molecular North America Patients Peripheral Physical activity Plasma Plasma Proteins Population Population Heterogeneity Population Study Positioning Attribute Preventive Proteins Psychosocial Stress Recording of previous events Reporting Research Resources Risk Risk Factors Role Serum Testing Therapeutic Trials Time Traction accurate diagnosis astrogliosis axon injury biomarker development clinical diagnosis clinical trial readiness cognitive function cohort design disease diagnosis effective therapy ethnic minority gray matter high risk imaging biomarker modifiable risk neglect neurofilament neuropathology non-genetic novel polygenic risk score prevent protective factors protein biomarkers racial minority racial population sex tau Proteins tau-1

项目摘要

Project 2 Summary for Overall The overarching goal of Project 2 is to enhance clinical trial readiness for ASAC. Successful identification of effective treatment and prevention for AD will require inclusion of all populations in clinical trials, with all individuals having accurate diagnosis of disease. Molecular measures of AD pathology have gained increasing traction to support clinical diagnosis of AD. Peripheral biomarkers, specifically plasma proteins that reflect AD neuropathology, have shown increasing utility and represent an accessible opportunity to diagnose and treat AD sooner. While no plasma biomarker has yet been approved for diagnostic use, blood biomarkers of AD neuropathology (Aβ42/40, Tau-181), axonal injury (neurofilament light [NfL]), and astrogliosis (glial fibrillary acidic protein [GFAP]) have shown promising utility in AD diagnosis given their strong associations with cognitive decline, gray matter loss, and AD conversion. However, most biomarker development has been performed in homogenous, European ancestry populations. There is an urgent need for the field to test whether AD biomarker thresholds generalize across diverse populations, including Asians. Meanwhile, it has been reported that 40- 50% of all dementia cases can be prevented by modifiable risk factors. Again, such findings are mainly based on studies focused mainly on European Americans and may not be generalized to ASAC. Prior studies have shown that effect sizes, and the relative contributions, of non-genetic risk factors on AD often differ between racial/ethnic groups. In addition, ASAC, being an ethnic minority living in North America, has unique risk profiles for AD compared to Asians living in Asia. Numerous non-genetic factors may contribute to such differences, including education, immigration history and acculturation level, leisure and physical activities, diet, and psychosocial stress. Better characterizing the risk profiles has critical implications for the design of future interventional trials for individuals with diverse ancestry, particularly for understudied groups like ASAC. To accurately identify those at highest risk for AD and to design an effective preventive trial, we require a better understanding of the impact of non-genetic factors on AD risk. Overall, Project 2 will address these gaps in knowledge by leveraging the unique resources of the multi-center ACAD to determine ASAC-specific diagnostic cut-offs for promising AD plasma biomarkers (Aβ42/40, Tau-181, NfL, and GFAP), and to investigate non-genetic factors in conferring AD risk and in moderating the association between genetic factors and AD in ASAC. Project 2 will test the overarching hypothesis that there are ASAC-specific AD biomarker thresholds and unique non- genetic factors that interact with genetic risk for AD. Together, through biomarkers and non-genetic factors (and integration with genetic factors in Project 1), Project 2 will generate a significant, sustained impact on the field by enhancing our ability to accurately profile AD risk in the ASAC community, which will be extremely valuable information when designing new interventions to prevent AD development and progression in all populations.

项目 2 总体总结项目 2 的总体目标是加强 ASAC 成功鉴定的临床试验准备。有效治疗和预防 AD 需要将所有人群纳入临床试验，对 AD 病理学进行准确诊断的个体已经越来越多。支持 AD 临床诊断的牵引力，特别是反映 AD 的血浆蛋白。神经病理学已显示出越来越多的实用性，并为诊断和治疗 AD 提供了可及的机会虽然尚未批准血浆生物标志物用于诊断，但 AD 的血液生物标志物已被批准用于诊断。神经病理学（Aβ42/40、Tau-181）、轴突损伤（神经丝光 [NfL]）和星形胶质细胞增生（神经胶质纤维鉴于酸性蛋白 [GFAP]）与认知能力密切相关，它们在 AD 诊断中显示出有前景的实用性然而，大多数生物标志物的开发都是在迫切需要在同质的欧洲血统人群中测试 AD 生物标志物。阈值适用于不同人群，包括亚洲人。同时，据报道，40- 50% 的痴呆症病例可以通过可改变的风险因素来预防。同样，这些发现主要基于。主要针对欧洲裔美国人的研究，可能无法推广到 ASAC 的先前研究。研究表明，非遗传风险因素对 AD 的影响大小和相对贡献通常在不同人群之间有所不同此外，ASAC 作为居住在北美的少数族裔，具有独特的风险特征。与生活在亚洲的亚洲人相比，许多非遗传因素可能会导致这种差异，包括教育、移民历史和文化适应水平、休闲和体育活动、饮食以及更好地描述风险状况对于未来的设计具有重要意义。针对具有不同血统的个体的干预试验，特别是针对像 ASAC 这样的研究不足的群体。准确识别 AD 风险最高的人群并设计有效的预防性试验，我们需要更好的方法总体而言，项目 2 将解决这些差距。通过利用多中心 ACAD 的独特资源来确定 ASAC 特定的诊断有希望的 AD 血浆生物标志物（Aβ42/40、Tau-181、NfL 和 GFAP）的截止值，并研究非遗传性 ASAC 项目中的 AD 风险因素以及调节遗传因素与 AD 之间关联的因素。 2 将测试总体假设，即存在 ASAC 特定的 AD 生物标志物阈值和独特的非通过生物标志物和非遗传因素与 AD 遗传风险相互作用的遗传因素。与项目 1) 中的遗传因素相结合，项目 2 将对该领域产生重大、持续的影响通过增强我们准确分析 ASAC 社区 AD 风险的能力，这将非常有价值设计新的干预措施以预防所有人群的 AD 发生和进展时的信息。