{
  "abstract": "BackgroundAlzheimers disease (AD) is a complex neurodegenerative disorder strongly influenced by genetic factors, with apolipoprotein E (APOE) {varepsilon}4 allele being the most established risk variant. Although DNA-based genotyping remains standard, plasma proteotyping may provide scalable, isoform-specific alternatives. Here, we aimed to investigate the clinical utility of APOE proteotyping as a surrogate for genotyping in different clinical and research cohorts.\n\nMethodsPlasma APOE4 protein were quantified using the NULISAseq CNS panel across four cohorts (ADRC, HeartSCORE, LATTICE, and ALPS). DNA-based APOE genotyping was the reference standard. Proteotyping thresholds for APOE {varepsilon}4 carrier status and copy number were derived in ADRC and externally validated in the other cohorts. Logistic, proportional-odds, and Cox proportional-hazards models compared genotype- and proteotype-defined groups in relation to amyloid positivity, cross-sectional CDR global scores, and time to CDR-SB worsening, respectively.\n\nResultsPlasma APOE4 accurately classified APOE {varepsilon}4 carrier status in ADRC (AUC=0.977, 95%CI 0.967-0.985; threshold 5.78 NULISA protein quantification [NPQ] value) and achieved near-perfect external validation in HeartSCORE, LATTICE, and ALPS (all AUCs=1.000, 95%CI 1.000-1.000). Plasma APOE4 also well-differentiated heterozygous from homozygous {varepsilon}4 carriers (ADRC AUC=0.879, 95%CI 0.834-0.921; threshold 12.23 NPQ value). Genotype- and proteotype-defined {varepsilon}4 carrier status showed similar associations with amyloid positivity (OR=4.40 vs 4.45), higher CDR global scores (OR=1.50 for both), and CDR-SB worsening (HR=1.22 for both).\n\nDiscussionPlasma APOE4 proteotyping accurately distinguished genotype-defined APOE {varepsilon}4 carrier status and copy number while demonstrating AD-related associations comparable to DNA genotyping.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA USA"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "R. Shi"
    },
    {
      "name": "L. T. Choity"
    },
    {
      "name": "M. F. Farinas"
    },
    {
      "name": "X. Zeng"
    },
    {
      "name": "J. E. Emanuel"
    },
    {
      "name": "A. Saeed"
    },
    {
      "name": "S. E. Reis"
    },
    {
      "name": "O. L. Lopez"
    },
    {
      "name": "M. I. Kamboh"
    },
    {
      "name": "A. D. Cohen"
    },
    {
      "name": "A. G. Gildengers"
    },
    {
      "name": "K. A. Wilckens"
    },
    {
      "affs": [
        0
      ],
      "name": "T. K. Karikari"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1fvn6wh8nx932.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.08.26364972",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.08.26364972v1.full",
  "id": "1fvn6wh8nx932",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.08.26364972v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7221443156",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.08.26364972v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1fvn6wh8nx932.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:38Z",
      "native_id": "10.64898/2026.10.08.26364972",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.08.26364972v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "Clinical utility of plasma APOE proteotyping for Alzheimer's disease risk and prognosis",
  "title_text": "Clinical utility of plasma APOE proteotyping for Alzheimer's disease risk and prognosis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:20:38Z",
  "url": "https://research.draconitic.com/paper/1fvn6wh8nx932",
  "venue": "medRxiv",
  "versions": []
}