Staging Alzheimer disease with blood-based biomarkers

阿尔茨海默病（AD）的大脑变化在认知症状发作前多年就开始了。最 AD模型提出了从淀粉样斑块沉积开始的脑病理学的逐步进展，然后 tau缠结形成，然后神经变性。脑脊液（CSF）和成像生物标志物已被 开发了允许在活体个体中检测AD脑病理的方法，但这些方法具有显著的 这些缺点限制了它们的广泛使用。在过去的三年里，发展迅速， 基于血液的生物标志物，准确检测AD脑病理。在这项研究中，我们建议研究 三种类型AD脑病理学的一些最有前途的基于血液的生物标志物：淀粉样蛋白 （Aβ42/Aβ40）、tau（磷酸化tau [pTau]亚型）和神经变性（神经丝轻 链蛋白[NfL]）。该研究小组已经开发了免疫沉淀-质谱分析， 血浆Aβ42/Aβ40和pTau亚型，将进一步优化和自动化，作为拟议的 项目将对Knight阿尔茨海默病研究中心的队列进行研究，并有以下可用数据： 血浆和CSF NfL，临床痴呆诊断，认知测试表现，健康史，淀粉样蛋白PET， tau PET，MRI脑结构体积，遗传标记，多种CSF生物标记测量，发现 蛋白质组学数据和尸检报告大约1，700对匹配的库存血浆和CSF 将对来自约1，000人的样本进行检查，这与最近的主要认知研究的规模相似。 结果作为生物标志物组合的函数。基于血液的测量与更好的 将对已建立的CSF和成像测量进行评价。淀粉样蛋白、tau蛋白和神经变性的生物标志物 将在一种模式（基于血液、CSF或成像）中单独使用和组合使用，以预测 当前或未来症状性AD的风险。对于所有分析，个体特征（包括 年龄、性别、受教育年限、APOE ε4基因型、多基因风险评分、种族和医学合并症） 评估以鉴定改变与生物标志物水平相关的症状表达的因素。我们 假设血浆Aβ42/Aβ40、pTau同种型和NfL的组合将比 淀粉样蛋白PET在预测当前或未来症状性AD风险中的作用因为血液测试被广泛接受， 患者，医生和研究人员，症状性AD的准确血液测试可能会被广泛使用 并可能成为改善AD研究，加速临床试验和实现更准确 诊断在诊所。

The brain changes of Alzheimer disease (AD) start many years before the onset of cognitive symptoms. Most models of AD propose a stepwise progression of brain pathology starting with amyloid plaque deposition, then tau tangle formation, then neurodegeneration. Cerebrospinal fluid (CSF) and imaging biomarkers have been developed that allow detection of AD brain pathology in living individuals, but these modalities have significant drawbacks that limit their widespread use. Over the last three years, there has been rapid development of blood-based biomarkers that accurately detect AD brain pathology. In this study, we propose to study some of the most promising blood-based biomarkers for three types of AD brain pathology: amyloid (Aβ42/Aβ40), tau (phosphorylated tau [pTau] isoforms), and neurodegeneration (neurofilament light chain protein [NfL]). The research team has developed immunoprecipitation-mass spectrometry assays for plasma Aβ42/Aβ40 and pTau isoforms that will be further optimized and automated as part of the proposed project. The Knight Alzheimer Disease Research Center cohort will be studied, and has available data on plasma and CSF NfL, clinical dementia diagnosis, performance on cognitive tests, health history, amyloid PET, tau PET, structural brain volumes by MRI, genetic markers, numerous CSF biomarker measures, discovery proteomics data, and autopsy reports. Approximately 1,700 matched pairs of banked plasma and CSF samples from ~1,000 individuals will be examined, which is similar in size to recent major studies of cognitive outcomes as a function of biomarker combinations. The correlation of the blood-based measures with better established CSF and imaging measures will be evaluated. Biomarkers of amyloid, tau and neurodegeneration will be used independently and in combination within a modality (blood-based, CSF or imaging) to predict the risk for current or future symptomatic AD. For all analyses, the effects of individual characteristics (including age, sex, years of education, APOE ε4 genotype, polygenic risk score, race, and medical comorbidities) will be evaluated to identify factors that modify the expression of symptoms associated with biomarker levels. We hypothesize that the combination of plasma Aβ42/Aβ40, pTau isoforms and NfL will perform better than amyloid PET in predicting risk for current or future symptomatic AD. Because blood tests are well-accepted by patients, physicians, and researchers, an accurate blood test for symptomatic AD would likely be widely used and could be a game-changer in improving AD research, accelerating clinical trials and enabling more accurate diagnoses in the clinic.