{
  "abstract": "Apolipoprotein E ( APOE ) genetic variation is the strongest genetic risk factor for late onset Alzheimer’s disease (LOAD). Studies on APOE genotype dependent changes have largely focused on amyloid beta (Aβ) aggregation, disease pathology, and lipid metabolism. Recently, there has been increased interest in the relationship between metabolic function and APOE genetic variation. In this study, we examined how APOE genotype can alter metabolism in the brains of young male and female APOE3 and APOE4 targeted replacement (TR) mice. In combination with this, we also examined cell type-specific differences using induced pluripotent stem cell (iPSC) derived astrocytes and neurons. We found sex and genotype dependent changes to metabolism in the brains of young APOE TR mice. Specifically, APOE4 mice show signs of metabolic stress and compensatory mechanisms in the brain. Using proteomics and stable isotope tracing metabolomics, we found that APOE4 iAstrocytes and iNeurons exhibit signs of inflammation, mitochondrial dysfunction, altered TCA cycle and malate-aspartate shuttle activity, and a metabolic shift toward glycolysis. Taken together, this data indicates APOE4 causes early changes to metabolism within the central nervous system. While this study establishes a relationship between APOE genotype and alterations in bioenergetics, additional studies are needed to investigate underlying mechanisms.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA",
    "University of Kansas Alzheimer’s Disease Research Center, Kansas City, KS, USA",
    "Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA",
    "Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA",
    "Kansas Center for Metabolism and Obesity Research, University of Kansas Medical Center, Kansas City, KS, USA",
    "Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA",
    "Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA",
    "Division of Molecular Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA",
    "Department of Internal Medicine, Division of Endocrinology, University of Kansas Medical Center, Kansas City, KS, USA"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Colton R Lysaker",
      "orcid": "0000-0002-9085-5285"
    },
    {
      "affs": [
        2,
        1
      ],
      "name": "Chelsea N. Johnson",
      "orcid": "0000-0003-2827-3265"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Vivien Csikós",
      "orcid": "0000-0003-3773-2582"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Edziu Franczak",
      "orcid": "0000-0002-0845-4002"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Maggie N. Benson"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Caleb A. Gilmore"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Cole J. Birky"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Xin Davis"
    },
    {
      "affs": [
        2,
        4
      ],
      "name": "Colin S. McCoin",
      "orcid": "0000-0002-8557-6441"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Keith P. Smith"
    },
    {
      "affs": [
        5
      ],
      "name": "Chad M Slawson",
      "orcid": "0000-0002-6886-4847"
    },
    {
      "affs": [
        6,
        7
      ],
      "name": "Peter A. Crawford",
      "orcid": "0000-0001-8597-4426"
    },
    {
      "affs": [
        7
      ],
      "name": "Patrycja Puchalska",
      "orcid": "0000-0002-1875-1203"
    },
    {
      "affs": [
        2,
        8,
        3,
        4,
        1
      ],
      "name": "John P. Thyfault",
      "orcid": "0000-0001-7920-7466"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Paige C. Geiger",
      "orcid": "0000-0002-3990-7246"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Jill K. Morris",
      "orcid": "0000-0001-5911-4190"
    },
    {
      "affs": [
        5,
        0,
        1
      ],
      "name": "Heather Wilkins",
      "orcid": "0000-0003-4563-4544"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5zt1mtr7sv14z.bib",
  "cited_by": 10,
  "doi": "10.1038/s44400-026-00105-8",
  "fulltext_url": null,
  "id": "5zt1mtr7sv14z",
  "issns": [
    "3005-1940"
  ],
  "landing_url": "https://doi.org/10.1038/s44400-026-00105-8",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ],
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      "openalex",
      "2804|Alzheimer's disease research and treatments"
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  "pdf_url": "https://www.nature.com/articles/s44400-026-00105-8.pdf",
  "pmcid": "PMC12262718",
  "pmid": "40666931",
  "published": "2026-07-01",
  "publisher": "Springer Science+Business Media",
  "ris": "https://research.draconitic.com/paper/5zt1mtr7sv14z.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T13:21:15Z",
      "native_id": "W7166863092",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s44400-026-00105-8"
    }
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    },
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology",
  "title_text": "APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:12Z",
  "url": "https://research.draconitic.com/paper/5zt1mtr7sv14z",
  "venue": "npj Dementia",
  "versions": []
}