Brittani R. Price, Keenan A. Walker, Jaclyn M. Eissman, Vidyani Suryadevara, Lindsey N. Sime, Timothy J. Hohman, Marcia N. Gordon
{"title":"性别差异和雌激素在阿尔茨海默病免疫基础中的作用","authors":"Brittani R. Price, Keenan A. Walker, Jaclyn M. Eissman, Vidyani Suryadevara, Lindsey N. Sime, Timothy J. Hohman, Marcia N. Gordon","doi":"10.1002/trc2.70139","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <p>Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone–immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).</li>\n \n <li>Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.</li>\n \n <li>Sex differences in innate and adaptive immunity could contribute to AD progression.</li>\n \n <li>Effects of menopausal hormone therapy on immunity in AD remain understudied.</li>\n \n <li>Future studies to explore sex differences in immune function during AD are needed.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 3","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70139","citationCount":"0","resultStr":"{\"title\":\"Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease\",\"authors\":\"Brittani R. Price, Keenan A. Walker, Jaclyn M. Eissman, Vidyani Suryadevara, Lindsey N. Sime, Timothy J. Hohman, Marcia N. Gordon\",\"doi\":\"10.1002/trc2.70139\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <p>Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone–immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Highlights</h3>\\n \\n <div>\\n <ul>\\n \\n <li>Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).</li>\\n \\n <li>Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.</li>\\n \\n <li>Sex differences in innate and adaptive immunity could contribute to AD progression.</li>\\n \\n <li>Effects of menopausal hormone therapy on immunity in AD remain understudied.</li>\\n \\n <li>Future studies to explore sex differences in immune function during AD are needed.</li>\\n </ul>\\n </div>\\n </section>\\n </div>\",\"PeriodicalId\":53225,\"journal\":{\"name\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"volume\":\"11 3\",\"pages\":\"\"},\"PeriodicalIF\":6.8000,\"publicationDate\":\"2025-08-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70139\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alzheimer''s and Dementia: Translational Research and Clinical Interventions\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70139\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","FirstCategoryId":"1085","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70139","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Sex differences and the role of estrogens in the immunological underpinnings of Alzheimer's disease
Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex-specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life-stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex-aware, personalized approaches to AD prevention and treatment. By integrating hormone–immune interactions with genetic and glial biology, this review emphasizes the critical need for sex-specific models in AD research.
Highlights
Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD).
Glial activation is adapted by estrogens to shape vulnerability or resilience to AD.
Sex differences in innate and adaptive immunity could contribute to AD progression.
Effects of menopausal hormone therapy on immunity in AD remain understudied.
Future studies to explore sex differences in immune function during AD are needed.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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