<p>Mechanical ventilation (MV) is an indispensable respiratory support strategy; however, increasing evidence suggests it may be a primary mediator of postoperative cognitive dysfunction (POCD) in vulnerable elderly patients. Despite this potential association, the precise lung–brain mechanisms through which MV-induced pulmonary stress mediates cognitive impairment and neurodegeneration remain unclear. To elucidate this interorgan cross-talk, we first conducted an observational analysis of plasma extracellular vesicles (EVs) from elderly surgical patients. We identified an association of general anesthesia, surgery, and MV with a marked postoperative increase in circulating EV-derived pTau217 levels, accompanied by a proteomic signature enriched in lung-related markers. In an aged murine MV model, we mapped the rapid lung-to-brain trajectory of pTau217-enriched extracellular vesicles (0–6&#xa0;h) and subsequent microglial activation and cognitive impairment. The results of integrated scRNA-seq and metabolomic profiling revealed that these EVs originated from bronchial epithelial cells, suggesting severe metabolic disturbance. The inhalation of hydrogen (H₂) effectively averted this metabolic crisis, thereby inhibiting local Tau hyperphosphorylation and halting the release of pTau217-enriched EVs. This upstream blockade subsequently prevented microglial activation and rescued cognitive performance. These findings define a pathological lung–brain axis in which MV-induced metabolic disruption drives the EV-mediated spread of pTau217 to precipitate POCD in aged mice. Importantly, H₂ therapy restores pulmonary metabolic homeostasis to halt this transmission at its source, suggesting a potential targeted intervention to preserve the aging brain in the perioperative period.</p> Graphical Abstract <p></p>