Moderate hypoxaemia and cognitive impairment in individuals with cigarette smoke exposure.

Background: Cognitive impairment (CI) is among the extrapulmonary comorbidities that are increasingly recognised in individuals with COPD and a history of cigarette smoke exposure. While severe hypoxaemia is a well-established risk factor for CI, the role of moderate hypoxaemia (peripheral oxygen saturation ( Methods: We evaluated the association between moderate hypoxaemia, assessed by pulse oximetry, and CI in participants from the Genetic epidemiology of COPD (COPDGene) study who completed the Phase 3 (10-year follow-up) visit. We performed mediation analysis of moderate hypoxaemia on the association between COPD and CI. We tested for differences in proteomic biomarkers of cerebral hypoxia and performed differential gene expression and pathway enrichment analyses to compare individuals with moderate hypoxaemia with those with CI. Findings: We found that moderate hypoxaemia at the 5-year follow-up visit, but not at the baseline visit, is associated with CI as assessed at the 10-year follow-up visit (OR 1.49, 95% confidence interval 1.10-1.99). In addition, moderate hypoxaemia significantly mediates the association between COPD and CI (average causal-mediated effect, 27.3%; p<0.001). Out of 38 proteins previously associated with cerebral hypoxia, 13 were significantly associated with moderate hypoxaemia. Interpretation: Our study establishes moderate hypoxaemia as an important risk factor for CI in individuals with a history of cigarette smoke exposure and as a mediator of the risk of CI in individuals with COPD. We also identify multi-omic biomarkers that better characterise the biological pathways underlying the association between moderate hypoxaemia and CI. Future studies are needed to identify individuals with moderate hypoxaemia who are at the highest risk of CI.