The development of blood-based biomarker tests that are accurate and robust for Alzheimer’s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. Plasma Aβ42/40 ratio was significantly (p < 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77–0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82–0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87–0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer’s disease; and may enhance the efficiency of enrolling participants into Alzheimer’s disease drug trials.

中文翻译：

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结合血浆 Aβ42/40 比率、ApoE 蛋白型和年龄的血液诊断测试可准确识别大脑淀粉样蛋白状态：多队列有效性分析的结果


开发针对阿尔茨海默病 (AD) 病理学准确且稳健的基于血液的生物标志物测试，有可能帮助临床诊断并促进 AD 药物试验的注册。我们开发了一种基于高分辨率质谱 (MS) 的测试，可量化血浆 Aβ42 和 Aβ40 浓度并鉴定 ApoE 蛋白型。我们评估了这种用于区分大脑淀粉样蛋白状态的 MS 生物标志物测定的稳健性、临床表现和商业可行性。我们使用新颖的 MS 测定法分析了 414 个血浆样本，这些样本是使用特定地点的协议从六个独立的美国队列中收集、处理和存储的。我们使用受试者工作特征曲线（ROC）分析来评估预测淀粉样蛋白状态（阳性、阴性和标准摄取值比率；SUVR）的检测性能和准确性。血浆分析后，各个部位共享大脑淀粉样蛋白状态，使用不同的、特定部位的方法和截止值来定义；使用各种示踪剂或 CSF Aβ42/40 比率进行淀粉样蛋白 PET 成像。每个队列中淀粉样蛋白阳性参与者的血浆 Aβ42/40 比率显着低于阴性参与者 (p < 0.001)。 ROC 曲线下面积 (AUC-ROC) 为 0.81 (95% CI = 0.77–0.85)，血浆 Aβ42/40 和淀粉样蛋白阳性之间的百分比一致性在最佳（约登指数）截止值时为 75%。控制队列异质性后，血浆 Aβ42/40 比率的 AUC-ROC（0.86；95% CI = 0.82–0.90）和准确性（81%）有所改善。当模型中包含 Aβ42/40、ApoE4 拷贝数和参与者年龄时，AUC-ROC（0.90；95% CI = 0.87–0.93）和准确度（86%）进一步提高。 这种基于质谱的血浆生物标志物测试：具有强大的诊断性能；能够准确区分大脑淀粉样蛋白阳性和淀粉样蛋白阴性个体；可能有助于阿尔茨海默病的诊断评估过程；并可能提高招募参与者参加阿尔茨海默病药物试验的效率。