{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:14:30Z","timestamp":1790612070069,"version":"4.1.0"},"posted":{"date-parts":[[2025,6,16]]},"group-title":"Neuroscience","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T00:00:00Z","timestamp":1750032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH"},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"crossref","award":["23AARG-1023294"],"award-info":[{"award-number":["23AARG-1023294"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"name":"VA","award":["1I01BX002567"],"award-info":[{"award-number":["1I01BX002567"]}]},{"name":"NIH","award":["P20 GM144269"],"award-info":[{"award-number":["P20 GM144269"]}]},{"name":"NIH","award":["P30AG072973"],"award-info":[{"award-number":["P30AG072973"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Apolipoprotein E (\n                  <jats:italic>APOE<\/jats:italic>\n                  ) genetic variation is the strongest genetic risk factor for late onset Alzheimer\u2019s disease (LOAD). Studies on\n                  <jats:italic>APOE<\/jats:italic>\n                  genotype dependent changes have largely focused on amyloid beta (A\u03b2) aggregation, disease pathology, and lipid metabolism. Recently, there has been increased interest in the relationship between metabolic function and\n                  <jats:italic>APOE<\/jats:italic>\n                  genetic variation. In this study, we examined how\n                  <jats:italic>APOE<\/jats:italic>\n                  genotype can alter metabolism in the brains of young male and female\n                  <jats:italic>APOE3<\/jats:italic>\n                  and\n                  <jats:italic>APOE4<\/jats:italic>\n                  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\n                  <jats:italic>APOE<\/jats:italic>\n                  TR mice. Specifically,\n                  <jats:italic>APOE4<\/jats:italic>\n                  mice show signs of metabolic stress and compensatory mechanisms in the brain. Using proteomics and stable isotope tracing metabolomics, we found that\n                  <jats:italic>APOE4<\/jats:italic>\n                  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\n                  <jats:italic>APOE4<\/jats:italic>\n                  causes early changes to metabolism within the central nervous system. While this study establishes a relationship between\n                  <jats:italic>APOE<\/jats:italic>\n                  genotype and alterations in bioenergetics, additional studies are needed to investigate underlying mechanisms.\n                <\/jats:p>","DOI":"10.1101\/2025.06.15.659811","type":"posted-content","created":{"date-parts":[[2025,6,16]],"date-time":"2025-06-16T12:40:15Z","timestamp":1750077615000},"source":"Crossref","is-referenced-by-count":8,"title":["Proteomic and metabolic profiling reveals\n                  <i>APOE4<\/i>\n                  -dependent shifts in whole brain, neuronal, and astrocytic mitochondrial function and glycolysis"],"prefix":"10.64898","author":[{"given":"Colton R.","family":"Lysaker","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chelsea N.","family":"Johnson","sequence":"additional","affiliation":[{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"},{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"Csikos","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edziu","family":"Franczak","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Kansas Center for Metabolism and Obesity Research, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Benson","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb A.","family":"Gilmore","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cole J.","family":"Birky","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Kansas Center for Metabolism and Obesity Research, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin S.","family":"McCoin","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Kansas Center for Metabolism and Obesity Research, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith P.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrycja","family":"Puchalska","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Crawford","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA"},{"name":"Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota Medical School, Minneapolis, MN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad","family":"Slawson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P.","family":"Thyfault","sequence":"additional","affiliation":[{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"},{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Kansas Center for Metabolism and Obesity Research, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige C.","family":"Geiger","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"Diabetes Institute, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill K.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather M.","family":"Wilkins","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA"},{"name":"University of Kansas Alzheimer\u2019s Disease Research Center, Kansas City, KS, USA"},{"name":"Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041203400847000_2025.06.15.659811v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00269-y"},{"key":"2026041203400847000_2025.06.15.659811v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2023.05.002"},{"key":"2026041203400847000_2025.06.15.659811v1.3","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.061509598"},{"key":"2026041203400847000_2025.06.15.659811v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199603213341202"},{"key":"2026041203400847000_2025.06.15.659811v1.5","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt204"},{"key":"2026041203400847000_2025.06.15.659811v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00180"},{"key":"2026041203400847000_2025.06.15.659811v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3266-12.2012"},{"key":"2026041203400847000_2025.06.15.659811v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20799"},{"key":"2026041203400847000_2025.06.15.659811v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2006.12.008"},{"key":"2026041203400847000_2025.06.15.659811v1.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.191044198"},{"key":"2026041203400847000_2025.06.15.659811v1.11","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-008-1039-z"},{"key":"2026041203400847000_2025.06.15.659811v1.12","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.662242"},{"key":"2026041203400847000_2025.06.15.659811v1.13","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e31827f0889"},{"key":"2026041203400847000_2025.06.15.659811v1.14","doi-asserted-by":"publisher","DOI":"10.1212\/01.WNL.0000148478.39691.D3"},{"key":"2026041203400847000_2025.06.15.659811v1.15","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000009582"},{"key":"2026041203400847000_2025.06.15.659811v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105781"},{"key":"2026041203400847000_2025.06.15.659811v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nature11087"},{"key":"2026041203400847000_2025.06.15.659811v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-022-01127-0"},{"key":"2026041203400847000_2025.06.15.659811v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2247-3"},{"key":"2026041203400847000_2025.06.15.659811v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/srep43701"},{"key":"2026041203400847000_2025.06.15.659811v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-61142-8"},{"key":"2026041203400847000_2025.06.15.659811v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112196"},{"key":"2026041203400847000_2025.06.15.659811v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41398-022-01881-6"},{"key":"2026041203400847000_2025.06.15.659811v1.24","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00483-y"},{"key":"2026041203400847000_2025.06.15.659811v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-023-01640-9"},{"key":"2026041203400847000_2025.06.15.659811v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s43587-021-00123-6"},{"key":"2026041203400847000_2025.06.15.659811v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2022.03.018"},{"key":"2026041203400847000_2025.06.15.659811v1.28","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07185-7"},{"key":"2026041203400847000_2025.06.15.659811v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.05.017"},{"key":"2026041203400847000_2025.06.15.659811v1.30","doi-asserted-by":"crossref","unstructured":"Budny V , Knopfli Y , Meier D , Zurcher K , Bodenmann C , Peter SL , et al. APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons. Cells. 2024;13(14).","DOI":"10.3390\/cells13141207"},{"key":"2026041203400847000_2025.06.15.659811v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.108572"},{"key":"2026041203400847000_2025.06.15.659811v1.32","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1400-19.2019"},{"key":"2026041203400847000_2025.06.15.659811v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.104742"},{"key":"2026041203400847000_2025.06.15.659811v1.34","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2019.00014"},{"key":"2026041203400847000_2025.06.15.659811v1.35","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113183"},{"key":"2026041203400847000_2025.06.15.659811v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00851-3"},{"key":"2026041203400847000_2025.06.15.659811v1.37","doi-asserted-by":"publisher","DOI":"10.1186\/1742-2094-8-175"},{"key":"2026041203400847000_2025.06.15.659811v1.38","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.29.17972"},{"key":"2026041203400847000_2025.06.15.659811v1.39","doi-asserted-by":"publisher","DOI":"10.1172\/JCI6172"},{"key":"2026041203400847000_2025.06.15.659811v1.40","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2024.1486762"},{"key":"2026041203400847000_2025.06.15.659811v1.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.11.004"},{"key":"2026041203400847000_2025.06.15.659811v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2018.10.029"},{"key":"2026041203400847000_2025.06.15.659811v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.10.015"},{"key":"2026041203400847000_2025.06.15.659811v1.44","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.ads0535"},{"key":"2026041203400847000_2025.06.15.659811v1.45","doi-asserted-by":"publisher","DOI":"10.1021\/ac403384n"},{"key":"2026041203400847000_2025.06.15.659811v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbpa.2015.11.009"},{"key":"2026041203400847000_2025.06.15.659811v1.47","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.0c02564"},{"key":"2026041203400847000_2025.06.15.659811v1.48","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa1011"},{"key":"2026041203400847000_2025.06.15.659811v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.039"},{"key":"2026041203400847000_2025.06.15.659811v1.50","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13775"},{"key":"2026041203400847000_2025.06.15.659811v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19264-0"},{"key":"2026041203400847000_2025.06.15.659811v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.06.011"},{"key":"2026041203400847000_2025.06.15.659811v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34412-4"},{"key":"2026041203400847000_2025.06.15.659811v1.54","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2023.1276506"},{"key":"2026041203400847000_2025.06.15.659811v1.55","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-023-00515-3"},{"key":"2026041203400847000_2025.06.15.659811v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0624-8"},{"key":"2026041203400847000_2025.06.15.659811v1.57","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15781"},{"key":"2026041203400847000_2025.06.15.659811v1.58","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.828648"},{"key":"2026041203400847000_2025.06.15.659811v1.59","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2024.1399965"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.06.15.659811","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T10:40:22Z","timestamp":1775990422000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.06.15.659811"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,16]]},"references-count":59,"URL":"https:\/\/doi.org\/10.1101\/2025.06.15.659811","relation":{},"subject":[],"published":{"date-parts":[[2025,6,16]]},"subtype":"preprint"}}