Accelerated midlife endocrine and bioenergetic brain aging in APOE4 females.

IF 4.5 2区医学 Q2 GERIATRICS & GERONTOLOGY

Frontiers in Aging Neuroscience Pub Date : 2025-08-18 eCollection Date: 2025-01-01 DOI:10.3389/fnagi.2025.1632877

Tian Wang, Zisu Mao, Yuan Shang, Simona Merlini, Francesca Vitali, Jean-Paul Wiegand, Roberta Diaz Brinton

{"title":"Accelerated midlife endocrine and bioenergetic brain aging in APOE4 females.","authors":"Tian Wang, Zisu Mao, Yuan Shang, Simona Merlini, Francesca Vitali, Jean-Paul Wiegand, Roberta Diaz Brinton","doi":"10.3389/fnagi.2025.1632877","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":12450,"journal":{"name":"Frontiers in Aging Neuroscience","volume":"17 ","pages":"1632877"},"PeriodicalIF":4.5000,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12399568/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Aging Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fnagi.2025.1632877","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"GERIATRICS & GERONTOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

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.

查看原文本刊更多论文

APOE4女性中年内分泌加速和生物能量脑老化。

女性性别、年龄和APOE4基因型是阿尔茨海默病的最大危险因素。利用基于人类生殖衰老阶段（STRAW）标准的翻译绝经期小鼠模型，我们研究了APOE基因型对女性中年内分泌衰老、外周代谢指标、脑生物能量途径、线粒体功能、神经免疫激活和髓鞘形成的影响。与APOE3雌性相比，APOE4雌性表现出加速的内分泌老化，这与无法进行适应性生物能量重编程和线粒体功能显著下降相一致，同时伴随着免疫激活和大脑脱髓鞘的增加。在女性中，APOE4与更年期提前有关。此外，APOE4基因的女性绝经早期患阿尔茨海默病的风险最高。这些结果提供了APOE4绝经后女性更早出现阿尔茨海默病和更大风险的合理机制途径。总的来说，这些发现支持中年是预防或延缓APOE4携带者阿尔茨海默病前驱期发病的关键窗口期。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Frontiers in Aging Neuroscience GERIATRICS & GERONTOLOGY-NEUROSCIENCES

CiteScore

6.30

自引率

8.30%

发文量

1426

期刊介绍： Frontiers in Aging Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the mechanisms of Central Nervous System aging and age-related neural diseases. Specialty Chief Editor Thomas Wisniewski at the New York University School of Medicine is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.