{
  "abstract": "The APOE locus is the strongest genetic factor for Alzheimer’s disease, with ε4 increasing and ε2 decreasing risk, yet the basis of these opposing effects remains unclear. Here we performed a multicohort proteomic analysis across plasma and cerebrospinal fluid in GNPC, BioFINDER-2, ADNI, UK BioBank, and PPMI. APOE -associated protein alterations are detectable before amyloid pathology and remain stable across age and disease progression. APOE2 -associated proteins were enriched in pathways related to cellular maintenance and anti-inflammatory processes. By contrast, APOE4 showed a limited set of upstream mediators linked to cell-cycle and oligodendrocyte precursor cell biology, and a broader group of proteins reflecting vascular, immune, and proteostatic dysfunction shaped by downstream pathology. Comparative analyses highlighted allele-specific mediators and oppositely regulated proteins contributing to differential disease risk. Together, these findings reveal that APOE2 and APOE4 shape Alzheimer’s disease risk through distinct molecular architectures and identify candidate biomarkers and targets for allele-specific interventions.",
  "abstract_shown": true,
  "affiliations": [
    "Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden. lina.lu@med.lu.se",
    "Centre de recherche de l'institut universitaire de gériatrie de Montréal (CRIUGM), Montréal, Quebec, Canada",
    "Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden",
    "Department of Physiology and Pharmacology, Université de Montréal, Montréal, Quebec, Canada",
    "Johnson & Johnson, Beerse, Belgium",
    "AbbVie, North Chicago, IL, USA",
    "Department of Clinical Sciences Malmö, SciLifeLab, Lund University, Lund, Sweden",
    "Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands",
    "Amsterdam Neuroscience, Neurodegeneration, Vrije Universiteit Amsterdam, Amsterdam, Netherlands",
    "Gates Ventures, Seattle, WA, USA",
    "Memory Clinic, Skåne University Hospital, Malmö, Sweden",
    "Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Faculty of Medicine, Lund University, Lund, Sweden. niklas.mattsson-carlgren@med.lu.se",
    "Memory Clinic, Skåne University Hospital, Malmö, Sweden. niklas.mattsson-carlgren@med.lu.se"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Lina Lu",
      "orcid": "0000-0001-9395-242X"
    },
    {
      "affs": [
        1,
        2,
        3
      ],
      "name": "Alexa Pichet Binette",
      "orcid": "0000-0001-5218-3337"
    },
    {
      "affs": [
        2
      ],
      "name": "Inès Hristovska",
      "orcid": "0009-0009-8676-5664"
    },
    {
      "affs": [
        2
      ],
      "name": "Shorena Janelidze",
      "orcid": "0000-0003-2869-8378"
    },
    {
      "affs": [
        4
      ],
      "name": "B. Smets"
    },
    {
      "affs": [
        2
      ],
      "name": "Irene Cumplido-Mayoral"
    },
    {
      "affs": [
        5
      ],
      "name": "Aparna Vasanthakumar",
      "orcid": "0000-0003-3857-8812"
    },
    {
      "affs": [
        5
      ],
      "name": "Britney Milkovich"
    },
    {
      "affs": [
        6
      ],
      "name": "Lijun An",
      "orcid": "0000-0003-1030-4625"
    },
    {
      "affs": [
        7,
        8,
        2
      ],
      "name": "Rik Ossenkoppele",
      "orcid": "0000-0003-1584-7477"
    },
    {
      "affs": [
        9
      ],
      "name": "Varsha S. Krish"
    },
    {
      "affs": [
        9
      ],
      "name": "Farhad B. Imam",
      "orcid": "0000-0003-2854-2568"
    },
    {
      "affs": [
        2,
        10
      ],
      "name": "Sebastian Palmqvist",
      "orcid": "0000-0002-9267-1930"
    },
    {
      "affs": [
        6
      ],
      "name": "Jacob W. Vogel",
      "orcid": "0000-0001-6394-9940"
    },
    {
      "affs": [
        2,
        10
      ],
      "name": "Erik Stomrud",
      "orcid": "0000-0002-0841-5580"
    },
    {
      "affs": [
        2
      ],
      "name": "Oskar Hansson",
      "orcid": "0000-0001-8467-7286"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "Niklas Mattsson",
      "orcid": "0000-0002-8885-7724"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b6g2wtrwt3cm6.bib",
  "cited_by": 9,
  "doi": "10.1038/s43587-026-01123-0",
  "fulltext_url": null,
  "id": "b6g2wtrwt3cm6",
  "issns": [
    "2662-8465"
  ],
  "landing_url": "https://doi.org/10.1038/s43587-026-01123-0",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2804|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7161235432",
  "pdf_url": null,
  "pmcid": "PMC12340876",
  "pmid": "40799961",
  "published": "2026-05-15",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/b6g2wtrwt3cm6.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T13:20:55Z",
      "native_id": "W7161235432",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s43587-026-01123-0"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    }
  ],
  "title": "Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer’s disease",
  "title_text": "Proteomic signatures of the APOE ε4 and APOE ε2 genetic variants and Alzheimer’s disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T13:20:55Z",
  "url": "https://research.draconitic.com/paper/b6g2wtrwt3cm6",
  "venue": "Nature Aging",
  "versions": []
}