Immune cell subsets linking insomnia trajectories and incident cognitive impairment: a prospective cohort study

BACKGROUND: This study aimed to examine the associations between insomnia trajectories and the risk of incident cognitive impairment, as well as to evaluate whether immune cell subsets mediate these associations. METHODS: A total of 6,316 participants aged 50 years or older from the Health and Retirement Study (HRS) were included in this prospective cohort study. Insomnia symptoms, including severe insomnia, difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), early morning awakening (EMA), and nonrestorative sleep (NRS), were assessed using the Jenkins Sleep Questionnaire. Longitudinal insomnia trajectories were identified from three examination waves during 2010-2016 (waves 10, 12 and 13) using latent class trajectory modeling. Incident cognitive impairment was defined according to the Langa-Weir cognitive status classification during 2016-2022 (waves 13-16). Data on immune cell subsets were obtained through flow cytometry of peripheral blood samples collected in the 2016 HRS Venous Blood Substudy. Cox proportional hazards models and mediation analyses were performed to assess associations. RESULTS: Trajectories of DIS, EMA, and NRS were significantly associated with increased risk of incident cognitive impairment. Compared to participants with persistently good trajectories, those with worsening trajectories demonstrated significantly elevated risks of cognitive impairment, with hazard ratios of 1.37 (95% confidence interval [CI]: 1.16, 1.61) for DIS; 1.26 (95% CI: 1.07, 1.48) for EMA; and 1.16 (95% CI: 1.00, 1.35) for NRS. Mediation analysis revealed seven specific immune cell subsets as mediators of the associations of insomnia trajectories (DIS, EMA, and NRS) with the risk of incident cognitive impairment: CD4 + T cells (central memory, CM), CD4 + T cells (Naive), CD4 + T cells (Effector Memory, Tem), CD8 + T cells, CD8 + T cells (CM), CD8 + T cells (TemRA) and NK Cells (CD56LO), accounting for 1.16% to 8.21% of the total effect. Sex-stratified analysis revealed distinct mediation patterns: CD4 + T cells (Tem) and CD8 + T cells mediated the associations in males, whereas CD4 + T cells (CM), CD8 + T cells (CM) mediated the associations in females. CONCLUSIONS: These findings reveal the associations of dynamic insomnia trajectories with cognitive health, and potential immune mechanisms, suggesting that maintaining healthy sleep patterns may mitigate neurodegenerative progression.