通过淀粉样蛋白和tau蛋白PET时钟评估的阿尔茨海默病血浆生物标志物变化的时间

Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks.

作者信息

Milà-Alomà Marta, Tosun Duygu, Schindler Suzanne E, Hausle Isabella, Petersen Kellen K, Li Yan, Dage Jeffrey L, Du-Cuny Lei, Saad Ziad S, Saef Benjamin, Triana-Baltzer Gallen, Raunig David L, Coomaraswamy Janaky, Baratta Michael, Meyers Emily A, Mordashova Yulia, Rubel Carrie E, Ferber Kyle, Kolb Hartmuth, Ashton Nicholas J, Zetterberg Henrik, Rosenbaugh Erin G, Sabandal Martin, Shaw Leslie M, Bannon Anthony W, Potter William Z

机构信息

Northern California Institute for Research and Education, San Francisco, CA, USA.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.

出版信息

Ann Neurol. 2025 Jun 20. doi: 10.1002/ana.27285.

DOI:10.1002/ana.27285

PMID:40539416

Abstract

OBJECTIVE

The objective of this study was to evaluate the timing of change of Alzheimer's disease (AD) plasma biomarkers (Aβ42/Aβ40, p-tau217, p-tau181, GFAP, and NfL) from six different assay platforms, alongside established AD biomarkers, using amyloid and tau positron emission tomography (PET)-based AD progression timelines.

METHODS

Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), including 784 individuals with longitudinal amyloid PET and 359 with longitudinal tau PET, were analyzed to estimate the age at amyloid and tau PET positivity, respectively. Longitudinal plasma biomarker measurements were available from 190 individuals with an estimated amyloid PET positivity age and from 70 individuals with an estimated tau PET positivity age. In a subset of 17 clinical progressors, age at tau PET positivity strongly predicted symptom onset, allowing for estimation of symptom onset age. Biomarker trajectories based on time from amyloid or tau PET positivity or symptom onset were modelled using Generalized Additive Mixed models. Time intervals of significant biomarker change and the earliest timepoints at which biomarkers exceeded predefined abnormality thresholds were identified.

RESULTS

All plasma biomarkers except NfL became abnormal prior to established thresholds for amyloid and tau PET positivity. Plasma Aβ42/Aβ40 became abnormal very early in both amyloid PET and tau PET timelines, while plasma GFAP became abnormal early in the tau PET timeline. Plasma Aβ42/Aβ40 levels plateaued, whereas plasma p-tau217, p-tau181, GFAP, and NfL levels increased throughout the modeled disease progression. Some variations in the timing of these changes were observed across different biomarker assays.

INTERPRETATION

These findings suggest that the plasma Aβ42/Aβ40 may be useful in identifying individuals with very low levels of amyloid pathology, whereas p-tau, GFAP, and NfL may be useful in staging disease progression. ANN NEUROL 2025.

摘要

目的

本研究的目的是使用基于淀粉样蛋白和tau正电子发射断层扫描（PET）的阿尔茨海默病（AD）进展时间线，评估来自六个不同检测平台的AD血浆生物标志物（Aβ42/Aβ40、p-tau217、p-tau181、GFAP和NfL）的变化时间，以及已确立的AD生物标志物。

方法

分析来自阿尔茨海默病神经影像学倡议（ADNI）的数据，包括784例有纵向淀粉样蛋白PET数据的个体和359例有纵向tau PET数据的个体，以分别估计淀粉样蛋白和tau PET阳性时的年龄。有190例估计淀粉样蛋白PET阳性年龄的个体和70例估计tau PET阳性年龄的个体有纵向血浆生物标志物测量数据。在17例临床进展者的子集中，tau PET阳性时的年龄强烈预测症状发作，从而可以估计症状发作年龄。使用广义相加混合模型对基于从淀粉样蛋白或tau PET阳性或症状发作开始的时间的生物标志物轨迹进行建模。确定了生物标志物显著变化的时间间隔以及生物标志物超过预定义异常阈值的最早时间点。

结果

除NfL外，所有血浆生物标志物在淀粉样蛋白和tau PET阳性的既定阈值之前就变得异常。血浆Aβ42/Aβ40在淀粉样蛋白PET和tau PET时间线中都很早就变得异常，而血浆GFAP在tau PET时间线中很早就变得异常。血浆Aβ42/Aβ40水平趋于平稳，而血浆p-tau２17、p-tau181、GFAP和NfL水平在整个建模的疾病进展过程中持续升高。在不同的生物标志物检测中观察到这些变化时间的一些差异。