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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>A marked reduction in estrogen levels during perimenopause substantially elevates the risk of Alzheimer\u2019s disease (AD) and cognitive dysfunction in women. While the endocrine etiology is well established, applying this understanding to effective clinical prevention remains difficult. Recent findings of diminished cerebral glucose metabolism and lower mitochondrial cytochrome oxidase activity in menopausal women have shifted research attention toward mitochondrial homeostasis disruption and neuroimmune\u2013inflammatory network imbalance as central mechanisms underlying menopausal cognitive decline. This article examines the characteristics and underlying mechanisms of mitochondrial and immune imbalances induced by estrogen withdrawal during menopause. Estrogen deficiency is shown to disrupt mitochondrial\u2013immune homeostasis, particularly via ER\u03b2-mediated mitochondrial oxidative phosphorylation system (OXPHOS) dysfunction and subsequent excessive activation of the NLRP3 inflammasome. The analysis further addresses enhanced inflammatory signaling resulting from excessive reactive oxygen species generation and mitochondrial DNA (mtDNA) release, as well as reduced synaptic plasticity due to impaired neurotransmitter synthesis and an inflammatory microenvironment. Additionally, the dysregulation of the estrogen-neuromodulatory system in menopausal cognitive decline is investigated. Recent studies demonstrate that intervention strategies targeting estrogen receptors, especially selective ER\u03b2 agonists, possess significant neuroprotective potential. Future approaches should incorporate biomarkers, including neuroimaging and genetic polymorphisms, to facilitate risk-stratified and individualized precision medicine. This integration may enhance the prevention or delay of menopause-associated cognitive decline in women.<\/jats:p>","DOI":"10.3390\/ijms27157003","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T12:32:43Z","timestamp":1785846763000},"page":"7003","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Estrogen Withdrawal-Induced Cognitive Impairment in Menopausal Women: Mechanisms and Prospects for Integrated Interventions"],"prefix":"10.3390","volume":"27","author":[{"given":"Tiantian","family":"Qiu","sequence":"first","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9299-0256","authenticated-orcid":false,"given":"Junying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayou","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10172","DOI":"10.1038\/s41598-024-60373-3","article-title":"Chronicling men-strual cycle patterns across the reproductive lifespan with real-world data","volume":"14","author":"Cunningham","year":"2024","journal-title":"Sci. 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