This article aims to reevaluate our approach to female vulnerability to Alzheimer’s disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ4 polymorphism (APOE ɛ4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach.

中文翻译：

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蓝斑基因座的性别差异：一种可以解释女性阿尔茨海默病风险增加的启发式方法

本文旨在重新评估我们对女性易患阿尔茨海默病 (AD) 的方法，并提出一个新假设，考虑到蓝斑-去甲肾上腺素 (LC-NA) 结构和功能的性别差异如何解释女性更容易患阿尔茨海默病的原因广告。我们特别关注蓝斑 (LC) 形态、雌激素缺乏、神经炎症、血脑屏障通透性、载脂蛋白 ɛ4 多态性 (APOE ɛ4) 和认知储备。LC-NA 系统的作用和性别差异是 AD 研究中两个最迅速出现的主题。目前的文献要么研究 LC，因为它是最早出现 AD 病理的大脑区域之一，要么承认雌激素的神经保护作用，以及这些雌性激素的丧失如何导致 AD 中的性别差异；然而，现有的研究忽略了同时检查这两个基本原理，因此我们的假设未确定。总的来说，这篇文章应该通过提供发人深省的联系来了解女性 LC-NA 系统的破坏、雌激素的下降和 AD 脆弱性之间的相互关系，从而有助于缓解当前围绕女性 AD 的挑战。因此，可能需要为女性和男性分别开发针对这种异质性疾病的治疗，