Peripheral inflammation offers significant but limited explanation for the association between sleep and cognition health: evidence from two longitudinal studies.

Sleep disturbances can trigger peripheral inflammatory responses, and both poor sleep and inflammation have been linked to cognitive impairment. However, whether peripheral inflammation mediates the association between sleep quality and cognitive health remains insufficiently tested. We analyzed data from two independent cohorts: 259,817 non-demented participants (mean age 58 years, 55.39% female, mean follow-up 10.29 years) from the UK Biobank (UKB) and 1,107 participants (mean age 74 years, 56.82% female, mean follow-up 4.17 years) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). At baseline, sleep quality was assessed using self-reported or caregiver-reported information. Peripheral blood lymphocyte count (LYM), neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), and serum C-reactive protein (CRP) were used as pragmatic peripheral inflammatory markers. Causal mediation analyses tested whether peripheral inflammation mediated the associations of sleep quality with cognitive performance and risk of incident dementia. In both cohorts, poor sleep quality was associated with higher levels of LYM, NEU, NLR and CRP (p < 0.001), and with lower cognitive function (p < 0.001). Poor sleep quality was also associated with an increased risk of incident dementia in UKB (p < 0.001), whereas this association was not significant in ADNI (p = 0.33). Higher NEU, NLR, and CRP levels were associated with lower cognitive function (UKB, p < 0.001; ADNI, p < 0.05) and increased risk of dementia (p < 0.001). In UKB, selected markers mediated the associations of sleep quality with fluid intelligence (p < 0.001), numeric memory score (p < 0.05), and risk of incident all-cause dementia and Alzheimer's disease (p < 0.001). However, the mediation proportions were limited (< 10%). In ADNI, no significant mediation was observed. These findings suggest that peripheral inflammation provides a statistically significant but quantitatively limited explanation for the association between sleep and cognitive health. Future studies should investigate additional mechanisms and potential intervention targets in more diverse cohorts.