{
  "abstract": "BackgroundPlasma p-tau217 identifies Alzheimers disease pathology, but performance in mixed cohorts may not extend to conditional tau-positivity dis-crimination within amyloid-positive individuals or to MRI-defined hippocampal neurodegeneration. We compared plasma prediction across PET- and MRI-defined AT(N) outcomes and conducted separate axis-specific assessments.\n\nMethodsThis retrospective secondary study used Alzheimers Disease Neuroimaging Initiative (ADNI) data. Tasks were amyloid positivity (A; 1,097 participants, 496 positive), tau positivity (T; 929, 195), T within A+ (361, 161), study-defined hippocampal neurodegeneration (N; 1,303, 248), and joint A+T+ (852, 161). Repeated nested cross-validation used fold-internal preprocessing and calibration. Post-hoc assessments comprised a Bio-Hermes A-axis staged random-forest analysis using Lilly p-tau217 and C2N A{beta}40/A{beta}42 (908 participants; 328 and 324 positive under the primary and alternative PET classifications), and an A4 ordinal p-tau217 analysis against an A4-specific medial-temporal tau-PET endpoint in A+ participants.\n\nResultsADNI random-forest AUROCs were 0.9425 (95% CI 0.9271-0.9562) for A, 0.9495 (0.9325-0.9645) for T, 0.8852 (0.8485-0.9163) for T within A+, 0.7865 (0.7553-0.8151) for N, and 0.9614 (0.9484-0.9726) for joint A+T+. At thresholds targeting 90% sensitivity, specificity was 87.5% for T overall and 60.7% within A+. In Bio-Hermes, adding A{beta}40 and A{beta}42 to p-tau217 increased AUROC from 0.894 to 0.916 (paired difference 0.022, 95% conditional interval 0.010- 0.035) and changed Brier score by -0.011 (-0.017 to -0.005); the alternative PET classification was concordant. In A4, ordinal p-tau217 had AUROC 0.7356 (95% CI 0.6775-0.7907), average precision 0.5657 (0.4732-0.6677), and Spearman{rho} = 0.4718 (0.3824-0.5528).\n\nConclusionsADNI identified task-dependent performance boundaries, particularly attenuated conditional T discrimination within A+. Separate-cohort evidence supported moderate single-marker conditional-T discrimination in A4 and modest complementary A-axis information from plasma A{beta} in Bio-Hermes, but only within those respective axes and assay implementations.",
  "abstract_shown": true,
  "affiliations": [
    "The University of Manchester"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "J. Xu"
    },
    {
      "name": "S. Michopoulou"
    },
    {
      "affs": [
        0
      ],
      "name": "F. Costen"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6hek8hww248ca.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.15.26365631",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365631v1.full",
  "id": "6hek8hww248ca",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365631v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ],
    [
      "openalex",
      "2738|Dementia and Cognitive Impairment Research"
    ]
  ],
  "openalex": "W7222969944",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365631v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-15",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/6hek8hww248ca.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:10Z",
      "native_id": "10.64898/2026.10.15.26365631",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.15.26365631v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments",
  "title_text": "Performance boundaries of plasma-centred prediction across PET- and MRI-defined AT(N): QC-first internal validation in ADNI with separate axis-specific assessments",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:10Z",
  "url": "https://research.draconitic.com/paper/6hek8hww248ca",
  "venue": "medRxiv",
  "versions": []
}