{
  "abstract": "APOE ε4 is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), but its contribution to disease pathogenesis remains incompletely understood. Here, we integrate proteomic profiling of plasma, cerebrospinal fluid (CSF), and brain tissue from over 10,000 individuals to define the immune phenotype associated with APOE ε4. We identify a conserved, allele dose-dependent pro-inflammatory immune signature across peripheral and central tissues independent of AD diagnosis. This signature is enriched in adaptive immune cells and white matter-resident glial and vascular cells. It also emerges in patient-derived cortical organoids prior to amyloid-β and tau pathology, supporting a causal, genotype-driven mechanism. Cross-tissue comparisons reveal shared innate and antiviral responses alongside tissue-specific immune signaling. Notably, a 12-week medical ketogenic diet partially reversed the APOE ε4 immune signature. These findings position immune dysregulation as an early and tractable driver of AD risk in APOE ε4 carriers with direct implications for targeted prevention strategies.",
  "abstract_shown": true,
  "affiliations": [
    "Neurodegeneration and Disease Modelling Laboratory Westmead Institute for Medical Research, The University of Sydney Westmead New South Wales Australia",
    "School of Medical Sciences, Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia",
    "Biomedical Proteomics Children's Medical Research Institute, The University of Sydney Westmead New South Wales Australia",
    "University of Kansas Alzheimer's Disease Research Centre University of Kansas Medical Center Kansas City Kansas USA",
    "Integrative Imaging Core University of Kansas Medical Center Kansas City Kansas USA",
    "Human Brain Microphysiology Systems Group, School of Biomedical Engineering, Faculty of Engineering The University of Sydney Sydney New South Wales Australia",
    "Gates Ventures Seattle Washington USA",
    "Autoimmunity and Amyloidosis Research Group Westmead Institute for Medical Research, The University of Sydney Westmead New South Wales Australia",
    "Department of Neurology University of Kansas School of Medicine Kansas City Kansas USA",
    "Department of Biochemistry and Molecular Biology University of Kansas Medical Center Kansas City Kansas USA",
    "University of Kansas Cancer Center University of Kansas Medical Center Kansas City Kansas USA",
    "Department of Cell Biology and Physiology University of Kansas Medical Center Kansas City Kansas USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Artur Shvetcov",
      "orcid": "0000-0003-0592-984X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shannon Thomson"
    },
    {
      "affs": [
        2
      ],
      "name": "Mark E. Graham"
    },
    {
      "affs": [
        3
      ],
      "name": "Brittany M Hauger"
    },
    {
      "affs": [
        3
      ],
      "name": "Jessica E. Keller",
      "orcid": "0000-0003-4855-0776"
    },
    {
      "affs": [
        4
      ],
      "name": "Christine J. Smoyer",
      "orcid": "0009-0002-3838-3257"
    },
    {
      "affs": [
        4
      ],
      "name": "Sarah E. Tague",
      "orcid": "0000-0001-9637-5701"
    },
    {
      "affs": [
        5
      ],
      "name": "Ann‐Na Cho",
      "orcid": "0000-0003-0047-8867"
    },
    {
      "affs": [
        6
      ],
      "name": "Farhad B. Imam",
      "orcid": "0000-0003-2854-2568"
    },
    {
      "affs": [
        6
      ],
      "name": "Varsha S. Krish"
    },
    {
      "affs": [
        3
      ],
      "name": "Matthew K. Taylor",
      "orcid": "0000-0002-4368-2705"
    },
    {
      "affs": [
        3
      ],
      "name": "Jonathan D. Mahnken"
    },
    {
      "affs": [
        3
      ],
      "name": "Debra K. Sullivan",
      "orcid": "0000-0003-1694-5829"
    },
    {
      "affs": [
        7,
        1
      ],
      "name": "Joanne H. Reed",
      "orcid": "0000-0002-7585-7848"
    },
    {
      "affs": [
        8,
        3
      ],
      "name": "Jeffrey Murray Burns",
      "orcid": "0000-0001-7609-8954"
    },
    {
      "affs": [
        9,
        3,
        10
      ],
      "name": "Chad M Slawson",
      "orcid": "0000-0002-6886-4847"
    },
    {
      "affs": [
        9,
        11,
        8,
        3
      ],
      "name": "Russell Howard Swerdlow",
      "orcid": "0000-0003-2948-7230"
    },
    {
      "affs": [
        9,
        8,
        3
      ],
      "name": "Heather Wilkins",
      "orcid": "0000-0003-4563-4544"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Caitlin A. Finney",
      "orcid": "0000-0002-9357-8316"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8yk387fae5vdc.bib",
  "cited_by": 6,
  "doi": "10.1002/alz.71714",
  "fulltext_url": null,
  "id": "8yk387fae5vdc",
  "issns": [
    "1552-5260",
    "1552-5279"
  ],
  "landing_url": "https://doi.org/10.1002/alz.71714",
  "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": "W7204760097",
  "pdf_url": "https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/alz.71714",
  "pmcid": "PMC12288544",
  "pmid": "40709278",
  "published": "2026-08-31",
  "publisher": "Wiley",
  "ris": "https://research.draconitic.com/paper/8yk387fae5vdc.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T13:20:36Z",
      "native_id": "W7204760097",
      "source": "openalex",
      "url": "https://doi.org/10.1002/alz.71714"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    }
  ],
  "title": "Cross‐tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease",
  "title_text": "Cross‐tissue immune profiling of APOE ε4 reveals early dysregulation in Alzheimer's disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T13:20:56Z",
  "url": "https://research.draconitic.com/paper/8yk387fae5vdc",
  "venue": "Alzheimer s & Dementia",
  "versions": []
}