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

AT（N）框架使用PET和/或CSF生物标志物来定义阿尔茨海默病（AD） 病理学和连续性;然而，其广泛实施受到高成本和 有限的可访问性。最近在主要是高加索人样本中的进展已经确定了血浆 AD生物标志物-即Aβ42/Aβ40和磷酸化tau（p-tau，例如p-tau 181， p-tau 217）-其对于检测异常Aβ和Tau是高度敏感和特异的。血浆p- tau对于AD诊断和向AD转化的预测特别有希望;然而，它们的 可能作为疾病进展的标志物和轻度认知功能障碍的风险预测因子 (MCI)/AD，特别是在受AD影响不成比例的种族/族裔少数群体中， 大部分尚未开发。在这里，我们的目标是使用有前途的血浆AD的轨迹， 生物标志物1）定义其自然史，2）其预测发展AD的风险的能力， 特异性认知障碍，3）确定其分子决定因素。我们建议 在5个时间点测量3，810名梅萨参与者的Aβ42/Aβ40和p-tau 217（检查1， 4、5、6和7）跨越22年，和人神经元细胞系，以实现以下特异性 目标：目标1。定量两种血浆AD生物标志物（p-tau 217和Aβ42/Aβ40），并确定 从45岁开始到100岁以上，它们随着年龄的变化而变化。目标2.确定基线的能力 和血浆AD生物标志物的纵向变化来预测未来的认知损害。目的 3.为了研究血管老化和认知能力下降相关基因组特征的影响， 我们之前发现的AD生物标志物。拟议的梅萨纵向研究 将血浆AD生物标志物与多组学数据、心脏代谢测量、脑 中晚期过渡期的影像学、认知测试和临床MCI/AD数据 是评估血浆AD生物标志物预测未来AD风险的关键下一步。 在种族和民族多样化的人群中， 早期AD发病机制中的因果分子过程，可以作为疾病的靶点， 修改干预措施。

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.