Chronic high-altitude hypoxia exacerbates cognitive impairment and Alzheimer’s disease pathology

Background Chronic hypoxia has been acknowledged as a significant risk factor for Alzheimer's disease (AD), yet the impact of high-altitude hypoxia on AD pathogenesis remains poorly understood. Objective This study aims to investigate the effects of chronic high-altitude hypoxia on cognitive function and AD-related pathology. Methods A cross-sectional cohort comprising 186 high-altitude migrants (HAM) and 378 high-altitude natives (HAN) was recruited for a preliminary assessment. We further conducted 101 HAM, 135 HAN, and 66 low-altitude controls (LA) for plasma biomarkers research. Plasma Aβ 40 , Aβ 42 , and T-tau levels were quantified by SIMOA. In parallel, APP/PS1 mice were exposed to hypobaric hypoxia (simulated at 5,500 m) or normoxia for 30 days, followed by behavioral tests, brain immunohistochemistry, and transcriptomic/proteomic analyses. Results HAM subjects exhibited significant deficits in Montreal Cognitive Assessment scores and delayed recall subscores compared to LA controls, with both measures showing a positive correlation with peripheral oxygen saturation (SpO₂). Notably, HAN showed preserved memory despite lower overall cognitive scores. Plasma levels of amyloid-β (Aβ) 40 , Aβ 42 , and Aβ 42 /Aβ 40 ratio were significantly lower in both HAM and HAN groups compared to the LA group. In mice, chronic hypoxia exacerbated hippocampal Aβ deposition and induced spatial memory decline. Multi-omics analyses revealed the upregulation of oxidative stress and neuroinflammatory pathways and identified S100A8/A9 as a potential key mediator in hypoxia-accelerated AD pathology. Conclusions Our findings demonstrate that chronic high-altitude hypoxia contributes to cognitive decline and AD-related pathological changes, likely mediated by Aβ burden and oxidative stress. High-altitude hypoxia might be an important environmental risk factor for AD.