Cognitive\nImpairment Mechanisms in High-Altitude Exposure:\nProteomic and Metabolomic Insights

High-altitude exposure can adversely affect neurocognitive\nfunctions;\nhowever, the underlying mechanisms remain elusive. Why and how does\nhigh-altitude exposure impair neurocognitive functions, particularly\nsleep? This study seeks to identify the molecular markers and mechanisms\ninvolved, with the goal of forming prevention and mitigation strategies\nfor altitude sickness. Using serum proteomics and metabolomics, we\nanalyzed blood samples from 23 Han Chinese plain dwellers before and\nafter six months of high-altitude work in Tibet. The correlation analysis\nrevealed biomarkers associated with cognitive alterations. Six months\nof high-altitude exposure significantly compromised cognitive function,\nnotably, sleep quality. The key biomarkers implicated include SEPTIN5,\nPCBP1, STIM1, UBE2L3/I/N, amino acids (l/d-aspartic\nacid and l-glutamic acid), arachidonic acid, and S1P. Immune\nand neural signaling were suppressed, with sex-specific differences\nobserved. This study innovatively identified GABA, arachidonic acid, l-glutamic acid, 2-arachidonoyl glycerol, and d-aspartic\nacid as biomarkers and elucidated the underlying mechanisms contributing\nto high-altitude-induced neurocognitive decline with a particular\nfocus on sleep disruption. These findings pave the way for developing\npreventive measures and enhancing adaptation strategies. This study\nunderscores the physiological significance of high-altitude adaptation,\nraising new questions about sex-specific responses and long-term consequences.\nIt sets the stage for future research exploring individual variability\nand intervention efficacy.