ArticleAnnals of clinical and translational neurology2026
A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone.
Article in Annals of clinical and translational neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone.Annals of clinical and translational neurology · 2026Article
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8 authors.
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Abstract
objectivePlasma p-Tau217 leaves 30%-50% of patients in an indeterminate "gray zone" often requiring Aβ-PET. We developed GRAD (Gatekeeper-Reflex for Alzheimer's Disease), a two-stage Aβ-positivity prediction model to improve classification while reserving Aβ-PET for residual uncertainty.
methodsGRAD was developed in 145 cognitively impaired ADNI participants and externally validated in 1644 cognitively unimpaired A4/LEARN participants. Stage 1 used p-Tau217 alone; probabilities between 0.25 and 0.75 were considered indeterminate. Stage 2 used L2-regularized logistic regression combining plasma-biomarkers, genetic and demographic features. Aβ-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 < 0.001), 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 < 0.001). 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 Aβ-PET for residual uncertainty. GRAD may reduce PET use and testing costs in memory-clinic triage, prevention-trial enrichment, and disease-modifying therapy workup.
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