Data_Sheet_1_Phosphorylated Tau 181 Serum Levels Predict Alzheimer’s Disease in the Preclinical Stage.pdf

BackgroundThere is an urgent need for cost-effective, easy-to-measure biomarkers to identify subjects who will develop Alzheimer’s disease (AD), especially at the pre-symptomatic stage. This stage can be determined in autosomal dominant AD (ADAD) which offers the opportunity to observe the dynamic biomarker changes during the life-course of AD stages. This study aimed to investigate serum biomarkers during different AD stages and potential novel protein biomarkers of presymptomatic AD.MethodsIn the first stage, 32 individuals [20 mutation carriers including 10 with AD, and 10 with mild cognitive impairment (MCI), and 12 healthy controls] from ADAD families were analyzed. All subjects underwent a complete clinical evaluation and a comprehensive neuropsychological battery. Serum samples were collected from all subjects, and antibody arrays were used to analyze 170 proteins in these samples. The most promising biomarkers were identified during this screening and were then measured in serum samples of 12 subjects with pre-MCI and 20 controls.ResultsThe serum levels of 13 proteins were significantly different in patients with AD or MCI compared to controls. Of the 13 proteins, cathepsin D, immunoglobulin E, epidermal growth factor receptor (EGFR), matrix metalloproteinase-9 (MMP-9), von Willebrand factor (vWF), haptoglobin, and phosphorylated Tau-181 (p-Tau181) correlated with all cognitive measures (R2 = −0.69–0.76). The areas under the receiver operating characteristic curve of these seven proteins were 0.71–0.93 for the classification of AD and 0.57–0.95 for the classification of MCI. Higher levels of p-Tau181 were found in the serum of pre-MCI subjects than in the serum of controls. The p-Tau181 serum level might detect AD before symptoms occur (area under the curve 0.85, sensitivity 75%, specificity 81.67%).ConclusionsA total of 13 serum proteins showed significant differences between subjects with AD and MCI and healthy controls. The p-Tau181 serum level might be a broadly available and cost-effective biomarker to identify individuals with preclinical AD and assess the severity of AD.

背景：针对开发出成本效益高、易于测量的生物标志物，以识别可能发展为阿尔茨海默病（AD）的患者，尤其是处于无症状阶段的个体，存在迫切需求。在常染色体显性AD（ADAD）中，这一阶段可以通过观察AD病程中生物标志物的动态变化来确立，从而提供了观察的机会。本研究旨在探讨不同AD阶段血清生物标志物以及无症状AD的潜在新型蛋白质生物标志物。方法：在第一阶段，分析了来自ADAD家族的32名个体[包括20名突变携带者，其中10名患有AD，10名患有轻度认知障碍（MCI），以及12名健康对照者]。所有受试者均接受了全面临床评估和综合神经心理学测试。收集了所有受试者的血清样本，并使用抗体阵列对这些样本中的170种蛋白质进行分析。在筛选过程中确定了最有希望的生物标志物，随后在12名前MCI阶段患者和20名对照者的血清样本中进行了测量。结果：与对照者相比，13种蛋白质在AD或MCI患者的血清水平中存在显著差异。在这13种蛋白质中，组织蛋白酶D、免疫球蛋白E、表皮生长因子受体（EGFR）、基质金属蛋白酶-9（MMP-9）、冯·维勒布兰特因子（vWF）、触珠蛋白以及磷酸化Tau-181（p-Tau181）与所有认知指标的相关性为R2 = -0.69–0.76。这七种蛋白质的受试者工作特征曲线下面积为0.71–0.93，用于AD的分类，为0.57–0.95，用于MCI的分类。在前MCI受试者的血清中检测到比对照者血清中更高的p-Tau181水平。p-Tau181血清水平可能能够在症状出现之前检测到AD（曲线下面积0.85，敏感性75%，特异性81.67%）。结论：共有13种血清蛋白质在AD和MCI患者与健康对照者之间存在显著差异。p-Tau181血清水平可能是一种广泛可用且成本效益高的生物标志物，用于识别具有临床前AD的个体并评估AD的严重程度。