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Using a translational perimenopause mouse model based on human Stages of Reproductive Aging Works (STRAW) criteria, we investigated the impact of APOE genotype on female midlife endocrine aging, peripheral metabolic indicators, brain bioenergetic pathways, mitochondrial function, neuroimmune activation, and myelination. Compared to APOE3 females, APOE4 females exhibited accelerated endocrine aging that was coincident with failure to mount adaptive bioenergetic reprogramming and significant decline in mitochondrial function that were coupled with increased immune activation and demyelination in brain. In women, APOE4 was associated with early menopause. Further, APOE4 women experiencing early menopause exhibited the highest risk of Alzheimer\u2032s. These results provide plausible mechanistic pathways underlying the earlier emergence and greater risk of Alzheimer\u2032s in APOE4 postmenopausal females. Collectively, these findings support midlife as a critical window for intervention to prevent or delay the onset of the prodromal stage of Alzheimer\u2032s disease in APOE4 carriers.<\/jats:p>","DOI":"10.3389\/fnagi.2025.1632877","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T05:28:49Z","timestamp":1755494929000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Accelerated midlife endocrine and bioenergetic brain aging in APOE4 females"],"prefix":"10.3389","volume":"17","author":[{"given":"Tian","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zisu","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Merlini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Vitali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Paul","family":"Wiegand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta Diaz","family":"Brinton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.15252\/embj.2019104073","article-title":"A novel approach to measure mitochondrial respiration in frozen biological samples.","volume":"39","author":"Acin-Perez","year":"2020","journal-title":"Embo J."},{"key":"B2","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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