All except NfL became abnormal prior to established thresholds for amyloid and tau PET positivity.
Plasma Aβ42/Aβ40 became abnormal very early in both amyloid and tau PET timelines.
Plasma GFAP became abnormal early in the tau PET timeline.
Plasma Aβ42/Aβ40 levels plateaued, while p-tau217, p-tau181, GFAP, and NfL levels increased throughout the modeled disease progression.
Variations in the timing of biomarker changes were observed across different assay platforms.
Simplified
OBJECTIVE: The objective of this study was to evaluate the timing of change of Alzheimer's disease (AD) (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;98:508-523.
Key numbers
7.9 years
Early Abnormality Timing for Aβ42/Aβ40
Time before amyloid PET positivity threshold.
73.7 years
Estimated Age at Tau PET Positivity
Mean age at which tau PET positivity was observed.
81.0 years
Estimated Age at Symptom Onset
Mean age at first clinical assessment indicating symptoms.
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H.K. has served on scientific advisory boards and/or as a consultant for ALZpath and Roche, and has given lectures sponsored by Fujirebio and Roche. J.L.D. has/is served/serving as a consultant or on advisory boards for AlzPath Inc., and Quanterix. J.L.D. has received research support from Fujirebio and Roche Diagnostics in the past two years. J.L.D. has stock or stock options in AlzPath Inc. Y.L. is the co-inventor of the technology “Novel Tau isoforms to predict onset of symptoms and dementia in Alzheimer’s disease” which is in the process of licensing by C2N. N.J.A has received speaking fees from Quanterix. These conflicts involved companies that are developers of the assays used in the study. M.M.A., D.T., S.E.S., I.H., K.K.P., L.D.C., Z.S.S., B.S., G.T.B., D.L.R., J.C., M.B., E.A.M., Y.M., C.E.R., K.F., H.K., E.G.R., M.S., L.M.S., A.W.B. and W.Z.P. have nothing to report.
