Epigenetic Regulation of BMAL1 with Sleep Disturbances and Alzheimer's Disease.

Background: An early symptom of Alzheimer’s disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles. Objective: To investigate if BMAL1, a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology. Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1, determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score). Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p = 0.015) and CERAD (t(94), p = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r = 0.20, p = 0.05) and CpG4 (r = 0.20, p = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r = 0.20 p = 0.05) and vocabulary (r = 0.22 p = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI, p = 0.03) and CpG5 (B = 0.04, 95% CI, p = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = –0.27, 95% CI, p = 0.02). Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle.