Trajectories of blood-based biomarkers of AD, their determinants, and ability to predict cognitive impairment

AD 血液生物标志物的轨迹、其决定因素以及预测认知障碍的能力

• 批准号: 10670494
• 负责人: YONGMEI LIU
• 金额: $ 81.89万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670494
• 关键词: 3-Dimensional; Affect; African American; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Biological Markers; Blood; Blood Vessels; Brain; Brain imaging; Caucasians; Cell Culture System; Cell Line; Chinese; Clinical; Cognitive; Communities; Coupled; DNA Methylation; Data; Deacetylase; Dementia; Diagnosis; Disease; Disease Marker; Disease Progression; Elderly; Epigenetic Process; Ethnic Origin; Future; Genomics; Gold; Hippocampus (Brain); Hispanic; Human; Image; Impaired cognition; In Vitro; Individual; Intervention; Investigation; Longitudinal Studies; Magnetic Resonance Imaging; Measures; Mediation; Modeling; Molecular; Multi-Ethnic Study of Atherosclerosis; Multiomic Data; Natural History; Neurocognitive; Neurons; Participant; Pathogenesis; Pathway interactions; Plasma; Play; Population Heterogeneity; Positron-Emission Tomography; Process; Race; Risk; Risk Factors; Role; SIRT1 gene; Sampling; Signal Pathway; Site; Testing; Thick; Time; Transcript; adjudicate; apolipoprotein E-4; base; blood-based biomarker; cardiometabolic risk; cardiometabolism; cognitive testing; cohort; cost; disorder risk; epigenomics; ethnic diversity; ethnic minority; experimental study; genome sequencing; insight; knock-down; lentiviral-mediated; longevity gene; middle age; mild cognitive impairment; monocyte; nerve stem cell; overexpression; predictive modeling; primary outcome; racial and ethnic; racial diversity; screening; sex; tau Proteins; tau-1; transcriptomics; whole genome; β-amyloid burden

The AT(N) framework uses PET and/or CSF biomarkers to define Alzheimer’s Disease (AD) pathology and continuum; however, its broad implementation is restricted by high cost and limited accessibility. Recent advances in primarily Caucasian samples have identified plasma AD biomarkers – namely, the ratio of Aβ42/Aβ40 and phosphorylated tau (p-tau, e.g. p-tau181, p-tau217) – that are highly sensitive and specific for detecting abnormal Aβ and Tau. Plasma p- tau is particularly promising for AD diagnosis and prediction of conversion to AD; yet, their potential as markers of disease progression and risk predictors for mild cognitive impairment (MCI)/AD, especially among racial/ethnic minorities who are disproportionately affected by AD, remains largely unexplored. Here, our objective is to use trajectories of promising plasma AD biomarkers to 1) define their natural history, 2) their ability to predict the risk of developing AD- specific cognitive impairment, and 3) to identify their molecular determinants. We propose to measure Aβ42/Aβ40 and p-tau217 in 3,810 MESA participants, across five time points (Exam 1, 4, 5, 6 & 7) spanning 22 years, and human neuronal cell lines to achieve the following specific aims: Aim 1. To quantify two plasma AD biomarkers (p-tau217 and Aβ42/Aβ40) and determine their changes with age starting from age 45 to 100+. Aim 2. To determine the ability of baseline and longitudinal changes in plasma AD biomarkers to predict future cognitive impairment. Aim 3. To examine effects of vascular aging and cognitive decline-associated genomic features, that we have previously identified, on AD biomarkers. The proposed MESA longitudinal study combining plasma AD biomarkers with multi-omics data, cardiometabolic measures, brain imaging, cognitive testing, and clinical MCI/AD data across the mid- to late-life transition period is a critical next step to evaluate the utility of plasma AD biomarkers to predict future risk of cognitive impairment in a racially and ethnically diverse population, and to identify candidate causal molecular processes in early AD pathogenesis that could serve as targets for disease- modifying interventions.

AT（N）框架使用PET和/或CSF生物标志物来定义阿尔茨海默氏病（AD） 病理和连续性；但是，其广泛的实施受高成本的限制，并且 有限的可访问性。主要高加索样品的最新进展已确定血浆 AD生物标志物 - 即，Aβ42/Aβ40和磷酸化的tau的比率（p-tau，例如p-tau181， p-tau217） - 高度敏感，特定于检测异常Aβ和TAU。血浆P- tau对于AD诊断和预测AD的预测特别有希望。但是，他们 潜力作为疾病进展的标志和轻度认知障碍的风险预测因素 （MCI）/AD，尤其是在受广告影响不成比例影响的种族/族裔少数民族中 仍然是意外的。在这里，我们的目标是使用诺言等离子广告的轨迹 生物标志物至1）定义其自然历史，2）他们预测发展ad的风险的能力 特定的认知障碍和3）确定其分子决定剂。我们建议 在3,810名MESA参与者中测量Aβ42/Aβ40和P-TAU217，在五个时间点（考试1， 4、5、6＆7）跨越22年，以及人类神经元细胞系以实现以下特定 目的：目标1。量化两个血浆AD生物标志物（P-TAU217和Aβ42/Aβ40） 他们的变化从45岁到100岁以上的年龄开始。目标2。确定基线的能力 血浆AD生物标志物的纵向变化，以预测未来的认知障碍。目的 3。检查血管衰老和认知下降相关的基因组特征的影响， 我们以前已经在广告生物标志物上确定了。拟议的台面纵向研究 将等离子体AD生物标志物与多矩数据，心脏代谢措施，大脑相结合 整个中期至后期过渡期的成像，认知测试和临床MCI/AD数据 是评估等离子AD生物标志物的实用性以预测未来风险的关键下一步 在大致和种族多元化的人群中的认知障碍，并确定候选人 早期AD发病机理中的因果分子过程，可以作为疾病的靶标 修改干预措施。