Extraceullar Vesicle Biomarkers for Prediction of Cognitive Decline, Ab and TAU Accumulation, and atrophy in Preclinical Alzheimer's Disease

在以前的研究中，我们的部门开创了一种方法来捕获富含神经元来源的血液细胞外囊泡（EVs）（通过使用神经元表面标记物（包括但不限于L1CAM）的免疫亲和力捕获来实现）或星形细胞来源（通过使用星形细胞表面标记物GLAST的免疫亲和力捕获来实现）。迄今为止，我们已经在AD和对照受试者中进行了大量的病例对照研究，测量了ev相关的β -淀粉样蛋白、tau/p-tau、Ser和Tyr磷酸化的IRS-1、突触标记物、线粒体蛋白和其他信号介质。我们已经发现了多种与疾病相关的差异，对于一些蛋白质来说，这些差异可能有效地区分了两组。此外，生物标志物异常可能出现在临床前阶段，并可能预测AD。我们最近在巴尔的摩老龄化纵向研究、威斯康星阿尔茨海默病预防登记和社区研究中的动脉粥样硬化风险的大型临床前队列中发现，EV生物标志物可以预测未来的认知能力下降和未来的AD诊断。

In previous studies, our section pioneered a methodology capturing blood Extracellular Vesicles (EVs) enriched for neuronal origin (achieved by immunoaffinity capture using neuronal surface markers, including, but not limited to, L1CAM), or astrocytic origin (achieved by immunoaffinity capture using astrocytic surface marker GLAST). To date, we have conducted scores of case control studies measuring EV-associated beta-amyloid, tau/p-tau, Ser and Tyr phosphorylated IRS-1, synaptic markers, mitochondrial proteins and other signaling mediators, in AD and control subjects. We have found multiple disease-associated differences that, for some proteins, may effectively discriminate between the two groups. In addition, biomarker abnormalities may be present at the preclinical stage and may predict AD. We recently showed that EV biomarkers predict future cognitive decline and future AD diagnosis in large preclinical cohorts from the Baltimore Longitudinal Study on Aging, the Wisconsin Registry for Alzheimer's Prevention, and the Atherosclerotic Risk in Communities studies. This project is seeking to further demonstrate the relationship between EV markers and other biomarkers for AD (especially amyloid and Tau PET, and MRI atrophy) in large preclinical cohorts. These studies are needed to assess longitudinal changes in EV markers and their potential to predict AD at the preclinical stage, track disease progression and predict conversion from MCI to AD. We are in the process of analyzing samples from a large cohort of participants in the Women's Health Initiative Memory Study - Long Life Study to assess the relationship of EV biomarkers with cognitive resilience in women and APOE e4 genotype. In addition, we have analyzed samples of individual with young-onset vs. older-onset AD from the Indiana ADRC. In the coming year, we will produce EV biomarker measurements and examine their relationship against cognitive performance, amyloid and tau PET deposition, MRI atrophy and clinical progression from MCI to AD dementia using longitudinal cohorts (Harvard Aging Brain Study and CHARIOT-PRO).