Moderate Hypoxemia and Cognitive Impairment in Individuals with Cigarette Smoke Exposure

Background Cognitive impairment (CI) is among the extrapulmonary comorbidities that are increasingly recognized in individuals with chronic obstructive pulmonary disease (COPD) and cigarette smoke exposure. While severe hypoxemia is a well-established risk factor for CI, the role of moderate hypoxemia (SpO 2 89–93%) is unknown. Methods We evaluated the association between moderate hypoxemia, assessed by pulse oximetry, and CI in participants from the COPDGene study who completed the Phase 3 (10-year follow-up) visit. We performed mediation analysis of moderate hypoxemia 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 between individuals with moderate hypoxemia and cognitive impairment. Findings We found that moderate hypoxemia at the 5-year follow-up visit, but not baseline visit, is associated with CI assessed at the 10-year follow-up visit (OR 1.49, 95% CI 1.10–1.99). Additionally, moderate hypoxemia significantly mediates the association of COPD and CI (average causal mediated effect 27.3%, p<0.001). Thirteen out of 38 proteins previously associated with cerebral hypoxia were significantly associated with moderate hypoxemia. Interpretation Our study establishes moderate hypoxemia as an important risk factor for CI in individuals with cigarette smoke exposure and mediator of the risk of CI in individuals with COPD. We further identify multi-omic biomarkers that better characterize the biological pathways underlying the association of moderate hypoxemia and CI. Future studies are needed to identify individuals with moderate hypoxemia at highest risk of CI.