Testosterone as a mediator of APOE4-linked sex differences in Alzheimer's disease

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-09-28 DOI:10.1016/j.intimp.2025.115588

Zhidan Shi , Lingzhi Wu , Chu Zhang , Xiaoqian Zeng , Guangzhe Yao , Xinqi He , Jiayi Hu , Tian Xie , Ling He

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引用次数: 0

Abstract

The pathological mechanisms and clinical manifestations of Alzheimer's disease (AD) exhibit significant gender differences, with a higher proportion of female AD patients. Women carrying the apolipoprotein E4 (APOE4) genotype face a markedly higher risk of developing the disease compared to men. APOE4 plays a crucial role in shaping these gender disparities by influencing the characteristic pathologies of AD. As the primary androgen, testosterone and its metabolites play a vital role in maintaining central nervous system homeostasis by interacting with steroid hormone receptors. Testosterone may mediate these effects through the androgen receptor (AR), participate in immune regulation, influence lipid metabolism, and interfere with the cholinergic system, thereby contributing to gender differences among APOE4 carriers. Key regulatory nodes include IL-17 and TGF-β. Furthermore, we synthesized clinical evidence linking testosterone replacement therapy to cognitive impairment, analyzed current research limitations and gaps in the field, and provided theoretical guidance for developing future targeted interventions and gender-specific therapeutic strategies.

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睾酮作为阿尔茨海默病apoe4相关性别差异的中介。

阿尔茨海默病（Alzheimer's disease， AD）的病理机制和临床表现存在显著的性别差异，女性AD患者的比例较高。携带载脂蛋白E4 （APOE4）基因型的女性患此病的风险明显高于男性。APOE4通过影响AD的特征性病理，在形成这些性别差异中起着至关重要的作用。作为主要雄激素，睾酮及其代谢物通过与类固醇激素受体相互作用，在维持中枢神经系统稳态中起着至关重要的作用。睾酮可能通过雄激素受体（AR）介导这些作用，参与免疫调节，影响脂质代谢，干扰胆碱能系统，从而导致APOE4携带者的性别差异。关键调控节点包括IL-17和TGF-β。此外，我们综合了睾酮替代疗法与认知障碍相关的临床证据，分析了该领域目前研究的局限性和差距，并为未来制定有针对性的干预措施和针对性别的治疗策略提供了理论指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.