Luckey Alison M, Robertson Ian H, Lawlor Brian, Mohan Anusha, Vanneste Sven
Lab for Clinical & Integrative Neuroscience, School of Psychology, Trinity College Dublin, Dublin, Ireland.
Global Brain Health Institute, Trinity College Dublin, Dublin, Ireland.
J Alzheimers Dis. 2021;83(2):505-522. doi: 10.3233/JAD-210404.
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 (APOEɛ4), 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.
本文旨在重新评估我们对女性易患阿尔茨海默病（AD）的研究方法，并提出一个新的假设，即考虑蓝斑-去甲肾上腺素（LC-NA）结构和功能的性别差异如何解释女性为何更易患AD。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（APOEɛ4）和认知储备。LC-NA系统的作用和性别差异是AD研究中两个迅速兴起的话题。当前的文献要么因为LC是最早出现AD病理的脑区之一而对其进行研究，要么承认雌激素的神经保护作用以及这些女性激素的丧失如何导致AD中出现的性别差异；然而，现有研究忽略了同时审视这两个理论依据，因此我们的假设仍未确定。总体而言，本文通过对女性LC-NA系统破坏、雌激素减少和AD易感性之间的相互关系提供发人深省的联系，应有助于缓解当前围绕女性AD的挑战。因此，对于这种异质性疾病的治疗可能需要分别针对女性和男性进行独特开发，并且可能需要精准医学方法。
