Sleep-wake modulation and pathogenesis of Alzheimer disease: Suggestions for postponement and treatment

Sleep-wake disorders are recognized as one of the earliest symptoms of Alzheimer disease (AD). Accumulating evidence has highlighted a significant association between sleep-wake disorders and AD pathogenesis, suggesting that sleep-wake modulation could be a promising approach for postponing AD onset. The suprachiasmatic nucleus (SCN) and the pineal hormone melatonin are major central modulating components of the circadian rhythm system. Cerebrospinal fluid (CSF) melatonin levels are dramatically decreased in AD. Interestingly, the number of neurofibrillary tangles in the hippocampus, which is one of the two major neuropathologic AD biomarkers, increases in parallel with the decrease in CSF melatonin levels. Furthermore, a decrease in salivary melatonin levels in middle-aged persons is a significant risk factor for the onset of the early stages of AD. Moreover, the disappearance of rhythmic fluctuations in melatonin may be one of the best biomarkers for AD diagnosis. Light therapy combined with melatonin supplementation is the recommended first-line treatment for sleep-wake disorders in AD patients and may be beneficial for ameliorating cognitive impairment. Sleep-wake cycle modulation based on AD risk gene presence is a promising early intervention for AD onset postponement.