Linking nocturnal blood oxygen, sleep spindles, and dementia: a retrospective cohort mediation analysis in middle-aged and older adults
Year: 2025
Type: article
Abstract: STUDY OBJECTIVES: Impaired spindle activity and hypoxia have been linked to dementia. However, their joint mechanism remains unclear. METHODS: We conducted a mediation analysis in 2023 adults from Sleep Heart Health Study Visit 1 with adjudicated dementia outcomes from the Framingham Offspring and Atherosclerosis Risk in Communities cohorts (median follow-up: 21.0 years; 394 events). Exposures included desaturation-removed SpO2 during non-rapid eye movement (NREM) sleep and hypoxic burden (cumulative desaturations ≥2% min/hour); mediators included spindle density, spindle chirp, and spindle-SO coupling phase. Time-to-dementia was modeled using Weibull survival regression with covariate adjustment and demographic stratification; evaluation metrics included C-index and time-dependent area under the curve. RESULTS: Mean age was 61.5 years; 50.1% were female. One non-White participant was excluded due to potential SpO2 measurement bias. Spindle density significantly mediated both exposures with strong model performance (C-index 0.78 [95% CI = 0.73 to 0.82]; AUC10 0.83 [95% CI = 0.71 to 0.95]). For NREM SpO2, a 90% versus 98% SpO2 was associated with increased spindle density and a 137.0-day delay to dementia diagnosis (95% CI = 10.6 to 352.1 days; p = .024; 26.6% mediated). For hypoxic burden, a 20th percentile (22.35% min/hour) versus 80th percentile (85.24% min/hour) burden was correlated with increased spindle density and a 43.4-day delay to dementia diagnosis (95% CI = 1.1 to 92.9 days; p = .046; 69.1% mediated). The SpO2 exposure-mediator correlation was unexpectedly negative, potentially from limited age variability and statistical suppression. Mediation effects remained consistent across covariates and subgroups. CONCLUSIONS: The oxygenation-spindle pathway may represent a physiologic mechanism for time-to-dementia and modifiable marker for established oxygenation interventions. Statement of Significance Sleep spindles and nocturnal hypoxia are each linked to dementia. However, prior work has not examined the mechanistic link between oxygenation and spindle density, or whether specific measures of impaired oxygenation or spindle characteristics mediate dementia risk. Using a large, community-based cohort with longitudinal dementia outcomes, we conducted one of the first mediation analyses testing the oxygenation-spindle-dementia pathway. Of three mediators, spindle density robustly mediated the association between oxygenation metrics and time-to-dementia across covariates and demographic stratification. Thus, spindle density may be a physiologically grounded, non-invasively measurable, and potentially modifiable marker of cognitive decline. Future work should evaluate this pathway in diverse populations and test whether spindle-targeted interventions can alter dementia risk among individuals with sleep-disordered breathing.
Source: SLEEP
Language: English
Subfield: Cognitive Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4417501965