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A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone
Parankusham, H.; Vanderlip, C.; Birkenbihl, C.; Krishna, E.; Ugboaja, C.; Budson, A.; Frank, B.. Annals of clinical and translational neurology, 2026-09-02
Topic: Brain proteins, microglia and lab models
ObjectivePlasma p-Tau217 leaves 30-50% of patients in an indeterminate "gray zone" often requiring A{beta}-PET. We developed GRAD (Gatekeeper-Reflex for Alzheimers Disease), a two-stage A{beta}+ prediction model to improve classification while reserving A{beta}-PET for residual uncertainty. MethodsGRAD was developed in 145 cognitively impaired ADNI participants and externally validated in 1,644 cognitively unimpaired A4/LEARN participants. Stage 1 used p-Tau217 alone; probabilities between 0.25-0.75 were considered indeterminate. Stage 2 used L2-regularized logistic regression combining plasma-biomarkers, genetic and demographic features. A{beta}-PET served as the reference standard (ADNI florbetapir SUVR>1.11; A4 Centiloid[≥]20). ResultsFull model AUC was 0.915 (95% CI, 0.859-0.961) internally and 0.879 (95% CI, 0.861-0.895) externally. In the external gray zone (n=630), Stage 2 improved discrimination over p-Tau217 alone (AUC 0.793 vs 0.719; P<.001), increased correct classification without PET from 41.4% to 56.2% and reduced PET referral from 35.9% to 24.3%. In the p-Tau181 subset (n=256), Stage 2 outperformed p-Tau181 (AUC 0.799 vs 0.597; P<.001). Overall, 89.0% of ADNI and 90.7% of A4/LEARN participants were classified without PET; modeled testing costs were 44-52% lower than p-Tau217 screening with PET confirmation of the gray zone. InterpretationReflex multimarker testing improves indeterminate p-Tau217 classification while retaining A{beta}-PET for residual uncertainty. GRAD may reduce PET use and testing costs in memory-clinic triage, prevention-trial enrichment, and disease-modifying therapy workup.
Key findings
- Overall, 89.0% of ADNI and 90.7% of A4/LEARN participants were classified without PET; modeled testing costs were 44-52% lower than p-Tau217 screening with PET confirmation of the gray zone.
Why it matters
This study developed a two-stage plasma biomarker model that classified more participants without amyloid PET and reduced modeled testing costs compared with p-Tau217 screening with PET confirmation of the gray zone. It concerns diagnostic testing strategy, not treating, curing or preventing Alzheimer's disease.
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Study details
- Participants630
- Effect sizeAUC 0.793; 41.4% to 56.2%; 35.9% to 24.3%
- Evidence strengthLow
How this study scored 44/100
Published in a peer-reviewed journal. Scored zero for study design and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 41 of the 94 points we could judge it on, which is 44 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Annals of clinical and translational neurology) |
| Journal's citation record | 1 / 4 | Annals of Clinical and Translational Neurology: journal h-index 97 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” 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 | 2 / 4 | 630 participants |
| Effect reported | 3 / 3 | Effect reported with a statistic (interval, p-value, ratio or similar) |
| Studied in people | 3 / 3 | Studied in people (participant count stated) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| 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 | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Alzheimer’s Disease Neuroimaging Initiative: h-index 18 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 8 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 41 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 41 of the 94 points we could judge it on is 44 out of 100. |
| Total | 44 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 7 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Parankusham, H., Vanderlip, C., Birkenbihl, C., Krishna, E., Ugboaja, C., Budson, A., et al. (2026). A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone. Annals of clinical and translational neurology. https://doi.org/10.64898/2026.02.03.26345302
Vancouver
Parankusham H, Vanderlip C, Birkenbihl C, Krishna E, Ugboaja C, Budson A, et al. A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone. Annals of clinical and translational neurology. 2026. doi:10.64898/2026.02.03.26345302.
BibTeX
@article{parankusham2026-7da4a6e3,
author = {Parankusham, H. and Vanderlip, C. and Birkenbihl, C. and Krishna, E. and Ugboaja, C. and Budson, A. and Frank, B.},
title = {{A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone}},
journal = {Annals of clinical and translational neurology},
year = {2026},
doi = {10.64898/2026.02.03.26345302},
url = {https://doi.org/10.64898/2026.02.03.26345302}
}
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