Oxygen sensing and homeostasis is indispensable for the maintenance of brain structural and functional integrity. Under low-oxygen tension, the non-diseased brain has the ability to cope with hypoxia by triggering a homeostatic response governed by the highly conserved hypoxia-inducible family (HIF) of transcription factors. With the advent of advanced neuroimaging tools, it is now recognized that cerebral hypoperfusion, and consequently hypoxia, is a consistent feature along the Alzheimer's disease (AD) continuum. Of note, the reduction in cerebral blood flow and tissue oxygenation detected during the prodromal phases of AD, drastically aggravates as disease progresses. Within this scenario a fundamental question arises: How HIF-driven homeostatic brain response to hypoxia “behaves” during the AD continuum? In this sense, the present review is aimed to critically discuss and summarize the current knowledge regarding the involvement of hypoxia and HIF signaling in the onset and progression of AD pathology. Importantly, the promises and challenges of non-pharmacological and pharmacological strategies aimed to target hypoxia will be discussed as a new “hope” to prevent and/or postpone the neurodegenerative events that occur in the AD brain.

氧气感应和体内平衡对于维持大脑结构和功能的完整性是必不可少的。在低氧张力下，未患病的大脑有能力通过触发由高度保守的低氧诱导转录因子家族 (HIF) 控制的稳态反应来应对低氧。随着先进的神经影像学工具的出现，现在人们认识到脑灌注不足，因此缺氧是阿尔茨海默病 (AD)连续体的一致特征。值得注意的是，在 AD 的前驱期检测到的脑血流量和组织氧合减少会随着疾病的进展而急剧恶化。在这种情况下，出现了一个基本问题：在 AD c 期间，HIF 驱动的稳态大脑对缺氧的反应如何“表现”连续性？从这个意义上说，本综述旨在批判性地讨论和总结目前关于缺氧和 HIF 信号传导参与 AD 病理学发病和进展的知识。重要的是，旨在针对缺氧的非药物和药物策略的承诺和挑战将作为预防和/或推迟 AD 大脑中发生的神经退行性事件的新“希望”进行讨论。