The importance of apolipoprotein E (APOE) in late-onset Alzheimer's disease (LOAD) has been firmly established, but the mechanisms through which it exerts its pathogenic effects remain elusive. In addition, the sex-dependent effects of APOE on LOAD risk and endophenotypes have yet to be explained. In this Review, we revisit the different aspects of APOE involvement in neurodegeneration and neurological diseases, with particular attention to sex differences in the contribution of APOE to LOAD susceptibility. We discuss the role of APOE in a broader range of age-related neurodegenerative diseases, and summarize the biological factors linking APOE to sex hormones, drawing on supportive findings from rodent models to identify major mechanistic themes underlying the exacerbation of LOAD-associated neurodegeneration and pathology in the female brain. Additionally, we list sex-by-genotype interactions identified across neurodegenerative diseases, proposing APOE variants as a shared etiology for sex differences in the manifestation of these diseases. Finally, we present recent advancements in 'omics' technologies, which provide a new platform for more in-depth investigations of how dysregulation of this gene affects the development and progression of neurodegenerative diseases. Collectively, the evidence summarized in this Review highlights the interplay between APOE and sex as a key factor in the etiology of LOAD and other age-related neurodegenerative diseases. We emphasize the importance of careful examination of sex as a contributing factor in studying the underpinning genetics of neurodegenerative diseases in general, but particularly for LOAD.

中文翻译：

---

APOE 对阿尔茨海默病和其他与年龄相关的神经退行性疾病的性别依赖性影响。

载脂蛋白 E ( APOE ) 在迟发性阿尔茨海默病 (LOAD) 中的重要性已得到证实，但其发挥致病作用的机制仍然难以捉摸。此外，APOE对 LOAD 风险和内表型的性别依赖性影响尚未得到解释。在这篇综述中，我们重新审视了 APOE 参与神经退行性疾病和神经系统疾病的不同方面，特别关注APOE对负载易感性的贡献的性别差异。我们讨论APOE的作用在更广泛的与年龄相关的神经退行性疾病中，并总结将 APOE 与性激素联系起来的生物学因素，利用啮齿动物模型的支持性发现来确定女性大脑中 LOAD 相关神经退行性疾病和病理恶化的主要机制主题。此外，我们列出了跨神经退行性疾病确定的性别与基因型相互作用，提出了APOE变异作为这些疾病表现中性别差异的共同病因。最后，我们介绍了“组学”技术的最新进展，为更深入地研究该基因的失调如何影响神经退行性疾病的发展和进展提供了一个新平台。总的来说，本综述中总结的证据强调了APOE和性别之间的相互作用是 LOAD 和其他与年龄相关的神经退行性疾病病因学的关键因素。我们强调仔细检查性别作为研究一般神经退行性疾病的基础遗传学的一个促成因素的重要性，特别是对于 LOAD。