Marta Milà-Alomà, Duygu Tosun, Suzanne E Schindler, Isabella Hausle, Kellen K Petersen, Yan Li, Jeffrey L Dage, Lei Du-Cuny, Ziad S Saad, Benjamin Saef, Gallen Triana-Baltzer, David L Raunig, Janaky Coomaraswamy, Michael Baratta, Emily A Meyers, Yulia Mordashova, Carrie E Rubel, Kyle Ferber, Hartmuth Kolb, Nicholas J Ashton, Henrik Zetterberg, Erin G Rosenbaugh, Martin Sabandal, Leslie M Shaw, Anthony W Bannon, William Z Potter
{"title":"淀粉样蛋白和Tau PET时钟评估阿尔茨海默病血浆生物标志物变化的时间","authors":"Marta Milà-Alomà, Duygu Tosun, Suzanne E Schindler, Isabella Hausle, Kellen K Petersen, Yan Li, Jeffrey L Dage, Lei Du-Cuny, Ziad S Saad, Benjamin Saef, Gallen Triana-Baltzer, David L Raunig, Janaky Coomaraswamy, Michael Baratta, Emily A Meyers, Yulia Mordashova, Carrie E Rubel, Kyle Ferber, Hartmuth Kolb, Nicholas J Ashton, Henrik Zetterberg, Erin G Rosenbaugh, Martin Sabandal, Leslie M Shaw, Anthony W Bannon, William Z Potter","doi":"10.1002/ana.27285","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Interpretation: </strong>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.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7000,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks.\",\"authors\":\"Marta Milà-Alomà, Duygu Tosun, Suzanne E Schindler, Isabella Hausle, Kellen K Petersen, Yan Li, Jeffrey L Dage, Lei Du-Cuny, Ziad S Saad, Benjamin Saef, Gallen Triana-Baltzer, David L Raunig, Janaky Coomaraswamy, Michael Baratta, Emily A Meyers, Yulia Mordashova, Carrie E Rubel, Kyle Ferber, Hartmuth Kolb, Nicholas J Ashton, Henrik Zetterberg, Erin G Rosenbaugh, Martin Sabandal, Leslie M Shaw, Anthony W Bannon, William Z Potter\",\"doi\":\"10.1002/ana.27285\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Interpretation: </strong>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.</p>\",\"PeriodicalId\":127,\"journal\":{\"name\":\"Annals of Neurology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":7.7000,\"publicationDate\":\"2025-06-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/ana.27285\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ana.27285","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Timing of Changes in Alzheimer's Disease Plasma Biomarkers as Assessed by Amyloid and Tau PET Clocks.
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.
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
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