Staging Alzheimer disease with blood-based biomarkers

阿尔茨海默病(AD)的大脑变化在认知症状出现之前多年就开始了。多数 阿尔茨海默病的模型提出了一种脑部病理的逐步进展，从淀粉样斑块沉积开始，然后 Tau缠结形成，然后是神经退化。脑脊液(CSF)和影像生物标志物已被 开发出了能够在活人中检测AD脑病理的方法，但这些模式具有重要的意义 限制其广泛使用的缺点。在过去的三年里，有了快速的发展 基于血液的生物标记物，准确检测AD的大脑病理。在这项研究中，我们建议研究 三种类型AD脑病理最有前景的血液生物标志物：淀粉样蛋白 (Aβ42/Aβ40)、tau(磷酸化tau[ptau]亚型)和神经变性(神经丝光 链蛋白[NFL])。该研究小组开发了免疫沉淀-质谱分析方法，用于 血浆Aβ42/Aβ40和PTAU亚型，将作为拟议的 项目。奈特阿尔茨海默病研究中心队列将被研究，并拥有关于 血浆和脑脊液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，遗传标记物，众多脑脊液生物标记物测量，发现 蛋白质组学数据和尸检报告。大约1700对匹配的储存血浆和脑脊液 来自大约1000个人的样本将被检查，这在大小上类似于最近关于认知的主要研究 作为生物标志物组合的函数的结果。血液学指标与优良率的相关性 将对已建立的脑脊液和成像措施进行评估。淀粉样蛋白、tau蛋白和神经退行性变的生物标志物 将在一种模式(基于血液、脑脊液或成像)中独立使用和组合使用，以预测 当前或未来出现症状性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、载脂蛋白Eε4基因型、多基因风险分数、种族和医疗合并症)将是 评估以确定改变与生物标记物水平相关的症状表达的因素。我们 假设血浆Aβ42/Aβ40、Ptau亚型和NFL的组合表现将好于 淀粉样蛋白PET在预测当前或未来症状性AD风险中的作用。因为血液测试很容易被 患者、医生和研究人员，对有症状的AD进行准确的血液测试可能会被广泛使用 在改进AD研究、加快临床试验和实现更准确的 诊所里的诊断结果。

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.