HABS-HD - Project 2

HABS-HD - 项目 2

• 批准号: 10708895
• 负责人: Sid E O'Bryant
• 金额: $ 41.28万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708895
• 关键词: Adult; African American population; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Anti-Inflammatory Agents; Biological Markers; Blood Vessels; Clinical; Clinical Trials; Cognition; Collaborations; Data; Disease Outcome; Elderly; Ethnic Origin; Ethnic Population; Etiology; Genetic Markers; Genotype; Health; Hispanic Populations; Impaired cognition; Inflammation; Inflammatory; Link; Medical; Metabolic; Mexican Americans; National Institute on Aging; Nerve Degeneration; Not Hispanic or Latino; Outcome; Participant; Pathway interactions; Pattern; Pharmaceutical Preparations; Population; Population Heterogeneity; Prediction of Response to Therapy; Prevalence; Proteomics; Race; Research; Risk; TREM2 gene; Testing; Work; aging brain; apolipoprotein E-4; burden of illness; comorbidity; dementia risk; diabetic; ethnic difference; experience; health disparity; middle age; mild cognitive impairment; neuroimaging; patient subsets; racial difference; racial population; tau Proteins; vascular factor

HABS-HD PROJECT 2 ABSTRACT Milestone 1.I of the NIA Alzheimer’s Disease (AD) + Alzheimer’s Disease-Related Dementias (ADRD) Implementation Milestones explicitly calls for testing “early mechanistic pathways of multiple etiologies that may account for AD/ADRD health disparities”. Significant health disparities exist in the U.S. related to AD with African Americans (AAs) currently suffering the highest burden of AD/ADRD while Hispanics (65% of which are Mexican American [MA]) will experience the greatest increase in disease burden by 20602. MAs also develop cognitive loss at significantly younger ages. Despite these factors, AAs and MAs remain underrepresented in AD research. In fact, 83% of participants in the National Institute of Aging (NIA) Alzheimer’s Disease Centers (ADC) and 90% of the Alzheimer’s Disease Neuroimaging Initiative (ADNI)7 are non-Hispanic white (NHW). Additionally, the 2018 AT(N) framework, which represents the mechanistic pathways (amyloid [A], tau [T], neurodegeneration [N]) dominating the current clinical trial landscape, was built almost entirely on data from NHWs who are screened out for most medical comorbidities. Nevertheless, emerging data demonstrates racial/ethnic differences in AT(N) defined biomarkers and, therefore, the applicability of the framework to AAs and MAs remains unknown, which is the focus of Project 1. AAs and MAs also suffer a heavier burden of vascular, metabolic and inflammatory (VMI) factors, each of which have well-established links to AD, including AT(N) biomarkers. Therefore, VMI factors may be targetable “early mechanistic pathways” that contribute to AD health disparities that cannot be understood without inclusion of populations known to experience the highest burden from them. Project 2 will evaluate the impact of VMI factors on the prevalence, sequence and trajectories of AT(N) defined biomarkers and cognitive loss among the three largest racial/ethnic groups in the U.S. Aim 1: Examine the impact of VMI factors on the presence and progression of cognitive loss among African Americans, Mexican Americans, and non-Hispanic whites. Aim 2: Examine the impact of VMI factors on the presence, sequence and trajectories of AT(N) defined biomarkers among African Americans, Mexican Americans, and non-Hispanic whites. Aim 3: Determine if VMI factors explain the racial/ethnic specific impact of APOEε4 genotype - and other VMI-related AD genetic markers - on AT(N) defined biomarkers. Aim 4 (Project – Project Interactions): Collaborate with Projects 1 and 3 to develop a comprehensive understanding of AT(N) defined biomarkers across diverse populations. Exploratory Aim 5: Compare VMI data and VMI – AT(N) interaction data with that from other large-scale initiatives such as ADNI, LEADS, ADCs, WHICAP, SOL/INCA, ABC-DS, MarkVCID, INDEED, and others.

HABS-HD 项目 2 摘要 NIA 阿尔茨海默病 (AD) + 阿尔茨海默病相关痴呆 (ADRD) 的里程碑 1.I 实施里程碑明确要求测试“多种病因的早期机制途径， 可能是 AD/ADRD 健康差异的原因”。美国存在与 AD 相关的显着健康差异。 非裔美国人 (AA) 目前遭受 AD/ADRD 负担最重，而西班牙裔美国人（其中 65% 患有 AD/ADRD） 到 20602 年，墨西哥裔美国人 [MA] 的疾病负担将增加最多。MA 也会发展 尽管存在这些因素，但 AA 和 MA 的代表性仍然不足。 事实上，国家老龄化研究所 (NIA) 阿尔茨海默病中心的参与者中有 83%。 (ADC) 和阿尔茨海默病神经影像计划 (ADNI)7 的 90% 是非西班牙裔白人 (NHW)。 此外，2018 AT(N) 框架代表了机制途径（淀粉样蛋白 [A]、tau [T]、 神经退行性疾病 [N]）在当前临床试验领域占据主导地位，几乎完全基于以下数据： 然而，新出现的数据表明，大多数医疗合并症都被筛查出来了。 AT(N) 定义的生物标志物中的种族/民族差异，以及该框架对 AA 的适用性 和 MA 仍然未知，这是项目 1 的重点。 AA 和 MA 也承受着沉重的负担 血管、代谢和炎症 (VMI) 因素，其中每一个因素都与 AD 有着明确的联系，包括 AT(N) 生物标志物因此，VMI 因素可能是有助于形成目标的“早期机制途径”。 如果不将已知经历 AD 的人群纳入其中，就无法理解 AD 健康差异 项目 2 将评估 VMI 因素对患病率、顺序的影响。 AT(N) 定义的生物标志物和三个最大种族/族裔之间的认知丧失的轨迹 美国团体目标 1：检查 VMI 因素对认知能力的存在和进展的影响 目标 2：检查非裔美国人、墨西哥裔美国人和非西班牙裔白人的损失。 VMI 影响非洲人定义的 AT(N) 生物标志物的存在、序列和轨迹 目标 3：确定 VMI 因素是否解释了美国人、墨西哥裔美国人和非西班牙裔白人。 APOEε4 基因型和其他 VMI 相关 AD 遗传标记对 AT(N) 的种族/民族特定影响 目标 4（项目 - 项目交互）：与项目 1 和 3 合作开发一个 全面了解不同人群中 AT(N) 定义的生物标志物。探索性目标 5： 将 VMI 数据和 VMI – AT(N) 交互数据与其他大型计划（例如 ADNI、 LEADS、ADC、WHICAP、SOL/INCA、ABC-DS、MarkVCID、INDEED 等。