Wang Tian, Mao Zisu, Shang Yuan, Merlini Simona, Vitali Francesca, Wiegand Jean-Paul, Brinton Roberta Diaz
Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, United States.
Department of Neurology, University of Arizona, Tucson, AZ, United States.
Front Aging Neurosci. 2025 Aug 18;17:1632877. doi: 10.3389/fnagi.2025.1632877. eCollection 2025.
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.
女性性别、年龄和APOE4基因分型是阿尔茨海默病最大的风险因素。我们基于人类生殖衰老阶段工作（STRAW）标准建立了一个围绝经期小鼠转化模型，研究了APOE基因分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雌性小鼠相比，APOE4雌性小鼠表现出加速的内分泌衰老，这与无法进行适应性生物能量重编程以及线粒体功能显著下降同时发生，而线粒体功能下降又与大脑中免疫激活增加和脱髓鞘有关。在女性中，APOE4与早绝经有关。此外，经历早绝经的APOE4女性患阿尔茨海默病的风险最高。这些结果为APOE4绝经后女性中阿尔茨海默病更早出现和更高风险提供了合理的机制途径。总体而言，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干预窗口。
