Interactive effects of retinal biomarkers and sleep on cognition: longitudinal evidence from community-dwelling older...

Retinal thickness has been proposed as a non-invasive biomarker of neurodegeneration, whereas sleep disturbances represent modifiable risk factors for cognitive impairment. However, the combined and temporal associations of these factors with cognition remain unclear. This prospective cohort study (2015-2022) included 257 participants aged ≥ 65 years. The retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GC-IPL) thickness, sleep variable (sleep quality and daytime sleepiness) were assessed at baseline. Cognitive performance, including global and domain-specific measures, was evaluated at baseline and biennially. Longitudinal associations and interaction effects were evaluated using multilevel generalized linear mixed models, with particular attention to quadrant-level variations. Elevated RNFL thickness was associated with better global cognition over time ( $\hat{\beta }$ : 0.39 × 10⁻²), with the strongest longitudinal positive associations observed in the temporal ( $\hat{\beta }$ : 17.89 × 10^-2) and nasal quadrants ( $\hat{\beta }$ : 18.67 × 10^-2). GC-IPL thickness showed a similar longitudinal association ( $\hat{\beta }$ : 0.60 × 10⁻²), which became more pronounced in participants with normal sleep quality ( $\hat{\beta }$ : 1.55 × 10^-2) or without excessive daytime sleepiness ( $\hat{\beta }$ : 0.81 × 10^-2). Furthermore, GC-IPL thickness significantly interacts with sleep quality (p_interation < 0.0001) and excessive daytime sleepiness (p_interation = 0.003). Retinal biomarkers showed quadrant-specific associations with cognition over time, and these associations were modified by sleep quality and daytime sleepiness. These findings underscore the potential of integrating retinal and sleep measures as early predictors of cognitive health, offering opportunities for targeted interventions in older adults.