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Estimating the time course of biomarker changes in Alzheimer's disease
Raket LL, Binette AP, Mattsson-Carlgren N, Janelidze S, Zetterberg H, Ashton NJ, Blennow K, Stomrud E et al.. Brain : a journal of neurology, 2026-06-01
Topic: Amyloid, tau and blood-test diagnosis
Plain-language summary
Recent advancements in biomarkers have transformed Alzheimer's disease (AD) diagnosis from being purely symptom-based to include biological criteria. With new treatments targeting the core biology of Alzheimer's disease, understanding the timeline of biological changes is crucial as the disease progresses over decades. Longitudinal data from amyloid-beta (Aβ) PET and cognitive tests [Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog)] from the Alzheimer's Disease Neuroimaging Initiative (n = 1448) and BioFINDER (n = 2088) were used to stage patients against an estimated continuous disease timeline (predicted time since Aβ-PET positivity). The estimated timeline was validated by comparing correlations with unseen biomarkers and cognitive measures against alternative staging approaches. Trajectories for plasma, CSF, MRI and PET biomarkers, measuring Aβ, tau and neurodegeneration, were mapped along this Alzheimer's disease continuum. The proposed staging approach was found to produce stronger correlations with unseen cognitive measures and biomarkers compared to alternative staging methods, including amyloid and tau PET clocks (all pairwise P < 0.05). Findings related to biomarker trajectories were highly consistent across cohorts. The period from Aβ-PET positivity to end-stage Alzheimer's disease dementia (MMSE = 0) was estimated at 20-25 years, with a presymptomatic phase of 7-11 years. CSF Aβ42/Aβ40 became abnormal about a year before Aβ-PET positivity, CSF phosphorylated-tau (p-tau)231, p-tau217 and plasma phosphorylated/neuritic plaque-tau217 1-3 years after, and tau-PET about 8 years after. Neurodegenerative biomarkers, such as hippocampal volume, became clearly abnormal in early dementia stages, 14-16 years after Aβ-PET positivity. The progression from initial biomarker abnormality to severe Alzheimer's disease spans two decades. Disease progression modelling elucidates the evolution of AD biomarkers and cognition, highlighting the relative timing of biomarker abnormalities. These models can determine disease stages, aiding in prognosis and the evaluation of disease-modifying treatments.
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APA 7th
Raket, L. L., Binette, A. P., Mattsson-Carlgren, N., Janelidze, S., Zetterberg, H., Ashton, N. J., et al. (2026). Estimating the time course of biomarker changes in Alzheimer's disease. Brain : a journal of neurology. https://doi.org/10.1093/brain/awaf413
Vancouver
Raket LL, Binette AP, Mattsson-Carlgren N, Janelidze S, Zetterberg H, Ashton NJ, et al. Estimating the time course of biomarker changes in Alzheimer's disease. Brain : a journal of neurology. 2026. doi:10.1093/brain/awaf413. PMID: 41178353.
BibTeX
@article{raket2026-41178353,
author = {Raket, L. L. and Binette, A. P. and Mattsson-Carlgren, N. and Janelidze, S. and Zetterberg, H. and Ashton, N. J. and Blennow, K. and Stomrud, E. and others},
title = {{Estimating the time course of biomarker changes in Alzheimer's disease}},
journal = {Brain : a journal of neurology},
year = {2026},
doi = {10.1093/brain/awaf413},
pmid = {41178353},
url = {https://doi.org/10.1093/brain/awaf413}
}
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Key findings
- The proposed staging approach was found to produce stronger correlations with unseen cognitive measures and biomarkers compared to alternative staging methods, including amyloid and tau PET clocks (all pairwise P < 0.05).
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Study details
- Study designlongitudinal study
- Participants1,448
- Evidence strengthModerate
How this study scored 76/100
Published in a leading specialty journal, and it is a longitudinal study following the same people over time. Scored zero for effect reported and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 44 of the 58 points we could judge it on, which is 76 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (Brain : a journal of neurology) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 7 / 12 | A longitudinal study following the same people over time |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 3 / 4 | 1,448 participants |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41178353) |
| Free to read | 2 / 2 | Free to read |
| Points | 44 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 44 of the 58 points we could judge it on is 76 out of 100. |
| Total | 76 / 100 | — |
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