ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 17 - 2025 | doi: 10.3389/fnagi.2025.1632877
Accelerated Midlife Endocrine and Bioenergetic Brain Aging in APOE4 Females
Provisionally accepted
Tian Wang1,2
Zisu Mao1
Yuan Shang1
Simona Merlini1,3Francesca Vitali1,2Jean-Paul Wiegand1
Roberta Diaz Brinton1,2,4*- 1Center for Innovation in Brain Science, University of Arizona, Tucson, United States
- 2Department of Neurology, College of Medicine, University of Arizona, Tucson, Arizona, United States
- 3Department of Biomedical Engineering, College of Engineering, University of Arizona, Tucson, Arizona, United States
- 4Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona, United States
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Female sex, age, and APOE4 genotype are the greatest risk factors for Alzheimer’s disease. 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’s. These results provide plausible mechanistic pathways underlying the earlier emergence and greater risk of Alzheimer’s 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’s disease in APOE4 carriers.
Keywords: Menopause, ApoE4, Women, Alzheimer's, Mitochondrial function, Neuroinflammation
Received: 21 May 2025; Accepted: 24 Jul 2025.
Copyright: © 2025 Wang, Mao, Shang, Merlini, Vitali, Wiegand and Brinton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Roberta Diaz Brinton, Center for Innovation in Brain Science, University of Arizona, Tucson, United States
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