{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T06:05:18Z","timestamp":1780380318831,"version":"3.54.1"},"reference-count":79,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["P01AG026572"],"award-info":[{"award-number":["P01AG026572"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Disruption of brain glucose and lipid metabolism contributes to Alzheimer\u2019s disease (AD) and often emerges before clinical symptoms. Women are at increased AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women\u2019s risk of AD is further exacerbated by the APOE4 allele, the strongest genetic risk factor for late-onset AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To investigate the impact of\n                      <jats:italic>APOE<\/jats:italic>\n                      genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3\/3, APOE3\/4, and APOE4\/4 mice across chronological and endocrinological stages from pre- to postmenopause.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>APOE3\/3 mice exhibited dynamic regulation of metabolic systems that supported postmenopausal brain bioenergetic demand. In contrast, APOE3\/4 and APOE4\/4 mice exhibited accelerated and compromised metabolic adaptation, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and compromised brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1796680","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T05:43:32Z","timestamp":1780379012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["APOE4 accelerates menopause-associated brain metabolic shift and disrupts bioenergetic adaptation"],"prefix":"10.3389","volume":"18","author":[{"given":"Tian","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Innovation in Brain Science, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Department of Neurology, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Shang","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"McLean","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Graduate Interdisciplinary Program in Neuroscience, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Yin","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Department of Pharmacology, College of Medicine Tucson, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta Diaz","family":"Brinton","sequence":"additional","affiliation":[{"name":"Center for Innovation in Brain Science, University of Arizona","place":["Tucson, AZ, United States"]},{"name":"Department of Pharmacology, College of Medicine Tucson, University of Arizona","place":["Tucson, AZ, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10101","DOI":"10.1073\/pnas.97.18.10101","article-title":"Singular value decomposition for genome-wide expression data processing and modeling.","volume":"97","author":"Alter","year":"2000","journal-title":"Proc. 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