0004 Associations of Accelerometer-Derived Circadian Sleep-Wake Abnormalities with Brain Health and Biomarker Pathways

Abstract Introduction Circadian sleep–wake abnormalities are common in older adults and frequently accompany neurodegenerative and psychiatric disorders. Evidence suggests that reduced circadian amplitude may be linked to conditions such as Parkinson’s disease and depression, independent of nocturnal sleep quality. However, it remains unclear whether circadian disruption precedes disease onset and contributes to risk through alterations in brain structure or blood-based biomarkers. Methods We analyzed wrist-worn accelerometer data from 95,552 participants in the UK Biobank prospective cohort and derived key circadian rhythm metrics using an extended cosine model, including amplitude, mesor, and acrophase. Brain health–related diseases were defined as psychiatric and neurodegenerative disorders using ICD-10 codes. Quality-controlled biomarker data from the UK Biobank imaging center and blood assays were incorporated, covering measures of brain structure, neurobiomarkers, blood counts, and blood biochemistry. Cox proportional hazards models were used to estimate associations between circadian metrics and incident diseases. Causal mediation analyses were performed to quantify the proportion of disease risk explained by each biomarker. Results Among 95,552 participants included in the analysis, 5,185 (5.4%) developed a brain health–related disease during 11 years of follow-up. After full adjustment, the risk of incident neurodegenerative diseases, most notably dementia, decreased with increasing circadian amplitude (HR, 0.71; 95% CI, 0.67–0.76) and mesor (HR, 0.89; 95% CI, 0.81–0.97), but increased with a delayed circadian phase (HR, 5.64; 95% CI, 2.18–14.56). For psychiatric disorders, particularly depression, risk decreased with higher circadian amplitude (HR, 0.88; 95% CI, 0.85–0.90), whereas increased with elevated mesor (HR, 1.12; 95% CI, 1.08–1.16) and an advanced circadian phase (HR, 1.60; 95% CI, 1.40–1.83). Causal mediation analyses showed that brain atrophy primarily mediated the association between circadian amplitude and neurodegenerative disease risk (proportion mediated, 0.16–0.85), whereas blood count and biochemical markers served as the main mediators for psychiatric disorders (proportion mediated,0.03–0.20). Conclusion Our findings indicate that circadian rhythm disruption exerts distinct effects on neurodegenerative and psychiatric disorders and may serve as an early indicator of disease onset. These results provide new insights for the prevention of related diseases. Support (if any)