{
  "abstract": "The apolipoprotein E ( APOE ) gene is the strongest genetic risk factor for Alzheimer’s disease (AD), influencing amyloid-β (Aβ) aggregation, clearance, and glial function. While APOE4 promotes Aβ pathology and APOE2 is protective, how these opposing alleles interact in the heterozygous APOE2/4 state remains unknown. Here, using littermate-controlled heterozygous APOE mice ( APOE2/3 , APOE3/4 , and APOE2/4 ) alongside APOE3/3 controls crossed with 5xFAD mice, we show that APOE3/4 mice exhibit increased Aβ deposition, maladaptive microglial activation, and reduced microglial interactions with plaques. These changes were attenuated in APOE2/4 mice, accompanied by a brain proteomic profile more similar to those of APOE3/3 and APOE2/3 mice. Increased myelin basic protein (MBP) abundance was observed in APOE2/3 but not APOE2/4 mice. Plasma lipidomics revealed shared alterations in APOE3/4 and APOE2/4 mice, with distinct signatures in APOE2/3 mice. These findings define allele interaction-dependent effects of APOE on brain and systemic phenotypes and provide a framework for understanding the biological consequences of the APOE2/4 genotype.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "name": "Kai Chen"
    },
    {
      "name": "Yixing Chen"
    },
    {
      "name": "Yingxue Ren",
      "orcid": "0000-0003-4529-5722"
    },
    {
      "name": "Zhen Wang"
    },
    {
      "name": "Ya Huang",
      "orcid": "0000-0002-9056-527X"
    },
    {
      "name": "Meixia Pan"
    },
    {
      "name": "Zonghua Li",
      "orcid": "0000-0001-5242-9608"
    },
    {
      "name": "Monica Castanedes Casey"
    },
    {
      "name": "Wenhui Qiao"
    },
    {
      "name": "Ji Shi"
    },
    {
      "name": "Dehui Kong"
    },
    {
      "name": "Gisela Xhafkollari",
      "orcid": "0000-0003-2486-7576"
    },
    {
      "name": "Hannah Santhakumar",
      "orcid": "0009-0008-4851-4437"
    },
    {
      "name": "Allison M. Wetmore"
    },
    {
      "name": "E. Aubrey Thompson",
      "orcid": "0000-0002-9001-4240"
    },
    {
      "name": "Xusheng Wang",
      "orcid": "0000-0002-1759-9588"
    },
    {
      "name": "Dennis W. Dickson",
      "orcid": "0000-0001-7189-7917"
    },
    {
      "name": "David M. Holtzman",
      "orcid": "0000-0002-3400-0856"
    },
    {
      "name": "Guojun Bu",
      "orcid": "0000-0003-3491-1016"
    },
    {
      "name": "Xianlin Han",
      "orcid": "0000-0002-8615-2413"
    },
    {
      "name": "Junmin Peng",
      "orcid": "0000-0003-0472-7648"
    },
    {
      "name": "Na Zhao",
      "orcid": "0000-0001-8648-9422"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/egtk1kk6q7q9q.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-78407-x",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13737102/",
  "id": "egtk1kk6q7q9q",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://www.nature.com/articles/s41467-026-78407-x",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7221019410",
  "pdf_url": "https://www.nature.com/articles/s41467-026-78407-x_reference.pdf",
  "pmcid": "PMC13737102",
  "pmid": "42982855",
  "published": "2026-10-08",
  "publisher": "Springer Science and Business Media LLC",
  "ris": "https://research.draconitic.com/paper/egtk1kk6q7q9q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:38Z",
      "native_id": "10.1038/s41467-026-78407-x",
      "source": "crossref",
      "url": "https://www.nature.com/articles/s41467-026-78407-x"
    },
    {
      "first_seen": "2026-11-09T12:22:24Z",
      "native_id": "PMC13737102",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41467-026-78407-x"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease",
  "title_text": "APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer’s disease",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:24Z",
  "url": "https://research.draconitic.com/paper/egtk1kk6q7q9q",
  "venue": "Nature Communications",
  "versions": []
}