Assessing the role of cerebrovascular brain injury and dysfunction in Alzheimer’s disease pathogenesis in the BEACoN Cohort

项目总结 在理解散发性阿尔茨海默病(AD)病因方面的一个关键差距是确定上游 导致阿尔茨海默氏症病理和相关神经功能障碍发展的因素。血管 在大约80%伴有AD病理的患者中发现了疾病，因此可能是一种 阿尔茨海默病发病的重要因素，然而，血管健康和 阿尔茨海默病的出现尚未在认知正常的情况下得到全面的研究 样本。虽然已知中风等大血管不良事件会增加发生血管病变的风险 痴呆症，越来越多的证据表明，在一生的伤害中积累的细微血管损伤可能 使神经结构和功能更容易受到AD相关病理生理学的影响。关键是， 慢性和细微形式的血管疾病更常见于黑人和西班牙裔人群， 减少了获得医疗保健的机会，这可能有助于解释这些人群中AD患病率上升的原因。 这个更新项目的目标是确定脑血管损伤和功能障碍(CVID)在 临床前阿尔茨海默病的病理生理学和开发个性化的基于成像的脑血管特征 预测不同种族和民族人群的记忆力下降。我们会继续跟进。 在我们目前的奖项中，对100名非痴呆老年人(60岁以上)的评估(Beacon Cohort： R01AG053555)，包括淀粉样PET(Florbetapir)、系列高分辨率MRI和tau-PET(MK-6240)， 我们的创新数字认知生物标记物可以评估模式分离，以及完整的UDS-3 神经心理测试组件。我们将通过有针对性的新招聘(n=100)来补充这一点 增加西班牙裔/拉丁裔和黑人参与者在我们队列中的代表性。我们已经建立了一个 基础设施，从根本上改变我们研究中的招聘和留住，包括与 在少数族裔招募方面有明显记录的临床研究机构。专注于细微之处 血管损伤，我们将排除基于中风或严重心血管疾病的病史。我们的目标是 (1)评估新的生物标志物框架，在该框架中，CVID预测tau的积累，其预测结构 和内侧颞叶(MTL)的功能恶化，随后预测 海马区模式分离。(2)构建基于个性化脑成像的CVID配置文件 在不同种族和民族的人群中，不同地预测海马体记忆的下降。(3)目标 3：将CVID档案与可修改的生活方式风险因素以及健康的结构性和社会决定因素相关联 在不同种族和民族之间有差异的分布。总而言之，我们将开发一部小说 CVID如何在AD病理生理和记忆/认知功能衰退中起作用的机制框架 直接解决阿尔茨海默病风险中的种族和民族差异。脑血管概况及其相关的 具有最大AD风险的可修改风险因素将被确定为未来干预的目标。

PROJECT SUMMARY A critical gap in understanding the etiology of sporadic Alzheimer's disease (AD) is identifying the upstream factors that lead to the development of both Alzheimer’s pathology and related neural dysfunction. Vascular disease is found in approximately 80% of patients with concomitant AD pathology and thus may be an important contributor to the development of AD, however relationships between vascular health and the emergence of AD pathophysiology has not yet been comprehensively investigated in cognitively normal samples. While large vascular adverse events such as stroke are known to confer risk for developing vascular dementia, growing evidence suggests that subtle vascular damage accrued through a lifetime of injury could predispose neural structure and function to become more susceptible to AD-related pathophysiology. Critically, chronic and subtle forms of vascular disease are more commonly found in Black and Hispanic populations with reduced access to healthcare and could help explain the increased prevalence of AD in these populations. The goal of this renewal project is to establish the role of cerebrovascular injury and dysfunction (CVID) in the pathophysiology of preclinical AD and develop individualized imaging-based cerebrovascular profiles that predict memory decline across racially and ethnically diverse populations. We will conduct follow-up assessments in 100 nondemented older adults (over 60 years of age) in our current award (BEACoN Cohort: R01AG053555), which includes amyloid-PET (florbetapir), serial high-resolution MRI and tau-PET (MK-6240), our innovative digital cognitive biomarkers which assess pattern separation, and a full UDS-3 neuropsychological testing battery. We will complement this with targeted new recruitment (n = 100) to increase the representation of Hispanic/Latino and Black participants in our cohort. We have built an infrastructure to radically transform recruitment and retention in our study including innovative partnerships with clinical research organizations with a demonstrable track record in minority recruitment. Given focus on subtle vascular damage, we will exclude based on history of stroke or severe cardiovascular disease. Our aims are (1) Assess the novel biomarker framework in which CVID predicts tau accumulation, which predicts structural and functional deterioration of the medial temporal lobes (MTL), subsequently predicting decline in hippocampal pattern separation. (2) Construct individualized brain imaging based CVID profiles that differentially predict decline in hippocampal memory across racially and ethnically diverse populations. (3) Aim 3: Associate CVID profiles with modifiable lifestyle risk factors and structural and social determinants of health that are differentially distributed across racial and ethnic groups. In summary, we will develop a novel mechanistic framework for how CVID contributes to AD pathophysiology and memory/cognitive decline that directly addresses racial and ethnic disparities in AD risk. Cerebrovascular profiles, and their associated modifiable risk factors that confer the greatest risk of AD, will be identified as targets for future intervention.