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

项目2总体摘要 项目2的总体目标是增强ASAC的临床试验准备。成功识别 有效治疗和预防阿尔茨海默病需要将所有人群纳入临床试验，所有 对疾病有准确诊断的个人。阿尔茨海默病的分子病理学研究进展 牵引以支持AD的临床诊断。外周生物标志物，特别是反映阿尔茨海默病的血浆蛋白 神经病理学已显示出越来越大的实用性，并为诊断和治疗阿尔茨海默病提供了一个可获得的机会 更快。虽然还没有血浆生物标记物被批准用于诊断，但AD的血液生物标记物 神经病理学(Aβ42/40，Tau-181)、轴突损伤(神经丝光)和星形胶质细胞增生症(胶质纤维 酸性蛋白[GFAP])在AD诊断中显示出良好的应用前景，因为它们与认知功能密切相关 衰退、灰质丢失和AD转换。然而，大多数生物标志物的开发都是在 同种的，欧洲血统的种群。该领域迫切需要测试AD生物标记物 门槛适用于不同的人群，包括亚洲人。与此同时，有报道称，有40- 50%的痴呆症病例可以通过可改变的危险因素来预防。同样，这些发现主要是基于 主要集中在欧洲美国人的研究上，可能不会推广到ASAC。先前的研究已经 结果表明，非遗传风险因素对阿尔茨海默病的影响大小和相对贡献通常不同于 种族/民族群体。此外，ASAC是生活在北美的少数民族，具有独特的风险特征 对于AD来说，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、饮食和 心理社会压力。更好地描述风险概况对未来的设计具有重要意义 针对不同血统个体的干预性试验，特别是对像ASAC这样研究不足的群体。至 准确识别AD的高危人群并设计有效的预防性试验，我们需要更好的 了解非遗传因素对AD风险的影响。总体而言，项目2将解决以下方面的差距 通过利用多中心ACAD的独特资源来确定特定于ASAC的诊断 有希望的AD血浆生物标记物(Aβ42/40、Tau-181、NFL和GFAP)的截断值，并调查非遗传性 在ASAC中，诱发AD风险的因素和调节遗传因素与AD之间的关联的因素。项目 2将检验压倒一切的假设，即存在ASAC特定的AD生物标志物阈值和唯一的非 与阿尔茨海默病遗传风险相互作用的遗传因素。通过生物标记物和非遗传因素(和 与项目1中的遗传因素相结合)，项目2将对实地产生重大的、持续的影响 通过增强我们在ASAC社区中准确描述AD风险的能力，这将是极其有价值的 在设计新的干预措施以防止所有人群中的阿尔茨海默病的发展和进展时提供信息。

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.