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Predicting the age of Alzheimer’s symptom onset from a blood test: evaluating a prognostic claim
Insel PS, Donohue MC.. medRxiv, 2026-04-01
Topic: Plasma and spinal-fluid biomarkers
Plain-language summary
Objectives Plasma p-tau217 clocks have been reported to predict when Alzheimer’s symptoms will begin, from a single blood test. This would transform Alzheimer’s research and care. We evaluated the prognostic value of these models. Design Analysis of a published prognostic study using data from two prospective longitudinal cohorts. Setting Two observational research cohorts: the Knight Alzheimer Disease Research Center (Knight ADRC), a single US centre, and the Alzheimer’s Disease Neuroimaging Initiative (ADNI), a multicentre study in the US and Canada. Participants 345 ADNI participants with longitudinal plasma %p-tau217 used to develop the clocks; 200 ADNI participants who were cognitively unimpaired (Clinical Dementia Rating 0) at blood draw; and 83 participants from both cohorts who progressed to symptomatic Alzheimer’s disease in the original report. Main Outcome Measures Age at symptom onset; time from %p-tau217 positivity to onset; time to onset from blood draw. Results The clock predictor, estimated age at %p-tau217 positivity, is age at blood draw minus estimated time since positivity, so age is shared by the predictor and the outcome, age at symptom onset. Separated from age, the clock’s %p-tau217 component explained essentially no variance (adjusted R² −0.02 to 0.02). Age alone explained 0.54 to 0.71, compared with 0.34 to 0.61 reported for the clock. Raw %p-tau217 with age outperformed the clock in every analysis. For time from positivity to onset, the reported shorter interval at older positivity ages was reproduced when the %p-tau217 component was replaced with a random number. In survival analysis, estimated age at positivity was associated with symptom onset age (hazard ratio 0.87, 95% confidence interval 0.81 to 0.95), but not when onset was measured from blood draw, removing the shared age component (1.02, 0.96 to 1.09). Conclusions The clock claims are unsupported. The reported accuracy comes from age shared between predictor and outcome, not from %p-tau217. Because timing is estimated only in known progressors, the model does not attempt to identify if an individual will progress, so it cannot answer the key question of when they will progress. Predictions from these models are unsupported for clinical or consumer use.
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APA 7th
Insel, P. S., & Donohue, M. C. (2026). Predicting the age of Alzheimer’s symptom onset from a blood test: evaluating a prognostic claim. medRxiv. https://doi.org/10.64898/2026.03.26.26349230
Vancouver
Insel PS, Donohue MC. Predicting the age of Alzheimer’s symptom onset from a blood test: evaluating a prognostic claim. medRxiv. 2026. doi:10.64898/2026.03.26.26349230.
BibTeX
@article{insel2026-7d6ebedf,
author = {Insel, P. S. and Donohue, M. C.},
title = {{Predicting the age of Alzheimer’s symptom onset from a blood test: evaluating a prognostic claim}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.03.26.26349230},
url = {https://doi.org/10.64898/2026.03.26.26349230}
}
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Key findings
- Results The clock predictor, estimated age at %p-tau217 positivity, is age at blood draw minus estimated time since positivity, so age is shared by the predictor and the outcome, age at symptom onset.
- Age alone explained 0.54 to 0.71, compared with 0.34 to 0.61 reported for the clock.
- In survival analysis, estimated age at positivity was associated with symptom onset age (hazard ratio 0.87, 95% confidence interval 0.81 to 0.95), but not when onset was measured from blood draw, removing the shared age component (1.02, 0.96 to 1.09).
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Study details
- Study designlongitudinal study
- Participants83
- Evidence strengthModerate
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 42 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for effect reported and randomized / blinded because the record does not state it. We have no data on 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 26 of the 62 points we could judge it on, which is 42 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| 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 | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 1 / 4 | 83 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 | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 26 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 26 of the 62 points we could judge it on is 42 out of 100. |
| Total | 42 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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