{
  "abstract": "Objective\n\nPlasma 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.Methods\n\nGRAD 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).Results\n\nFull 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.Interpretation\n\nReflex 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Physiology and Neurobiology, UConn Computational Biology Core, University of Connecticut, Storrs, Connecticut, USA.",
    "Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, USA.",
    "Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
    "Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut, USA.",
    "Yale School of Medicine, Yale New Haven Health, New Haven, Connecticut, USA.",
    "VA Boston Healthcare System, Boston, Massachusetts, USA.",
    "Alzheimer's Disease Research Center, Boston University Chobanian and Avedisian School of Medicine, Boston, Massachusetts, USA."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Harthik Parankusham",
      "orcid": "0009-0006-2796-1436"
    },
    {
      "affs": [
        1
      ],
      "name": "Casey Vanderlip",
      "orcid": "0000-0002-8233-5829"
    },
    {
      "affs": [
        2
      ],
      "name": "Colin Birkenbihl",
      "orcid": "0000-0002-7212-7700"
    },
    {
      "affs": [
        3
      ],
      "name": "Eashwar Krishna"
    },
    {
      "affs": [
        4
      ],
      "name": "Chizobam Ugboaja"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Andrew E Budson"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Brandon Frank"
    },
    {
      "name": "Alzheimer's Disease Neuroimaging Initiative"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1vgnq5ghye9dh.bib",
  "cited_by": 0,
  "doi": "10.1002/acn3.70560",
  "fulltext_url": "https://europepmc.org/articles/PMC13680551",
  "id": "1vgnq5ghye9dh",
  "issns": [
    "2328-9503"
  ],
  "landing_url": "https://europepmc.org/article/MED/42897700",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2738|Dementia and Cognitive Impairment Research"
    ]
  ],
  "openalex": "W7128441898",
  "pdf_url": "https://europepmc.org/articles/PMC13680551?pdf=render",
  "pmcid": "PMC13680551",
  "pmid": "42897700",
  "published": "2026-10-19",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1vgnq5ghye9dh.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:32Z",
      "native_id": "MED:42897700",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42897700"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2738|Dementia and Cognitive Impairment Research",
      "subfield": "psychiatry"
    }
  ],
  "title": "A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone.",
  "title_text": "A Two-Stage Plasma Biomarker Algorithm Reduces Amyloid PET Use and the p-Tau217 Gray Zone.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:32Z",
  "url": "https://research.draconitic.com/paper/1vgnq5ghye9dh",
  "venue": "Annals of clinical and translational neurology",
  "versions": []
}