The Circadian System in Alzheimer’s Disease: Disturbances, Mechanisms, and Opportunities

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative condition associated with severe cognitive and behavioral impairments. Circadian rhythms are recurring cycles that display periods of approximately 24 hours and are driven by an endogenous circadian timekeeping system centered on the suprachiasmatic nucleus of the hypothalamus. We review the compelling evidence that circadian rhythms are significantly disturbed in AD and that such disturbance is of significant clinical importance in terms of behavioral symptoms. We also detail findings from neuropathological studies of brain areas associated with the circadian system in postmortem studies, the use of animal models of AD in the investigation of circadian processes, and the evidence that chronotherapeutic approaches aimed at bolstering weakened circadian rhythms in AD produce beneficial outcomes. We argue that further investigation in such areas is warranted and highlight areas for future research that might prove fruitful in ultimately providing new treatment options for this most serious and intractable of conditions.

Dysrhythmia in the suprachiasmatic nucleus inhibits memory processing

“…This also appears to be the case for SCN control of memory processing. A number of studies have proposed that cognitive impairments caused by circadian dysfunction in humans are due to SCN cell loss or degeneration (5), but data from PSCNx hamsters suggest that cell loss is not a direct cause of these impairments. Instead, gradual cell loss in humans might lead to changes in the remaining SCN circuitry that actively restrict the brain's ability to form new memory representations (25).…”

Physiological Levels of Melatonin Relate to Cognitive Function and Depressive Symptoms: The HEIJO-KYO Cohort

“…Accumulating evidence suggests that misalignment in circadian biological rhythmicity may predispose to dementia and depression (12,13). Melatonin, a pineal gland hormone, is a biomarker of circadian biological rhythmicity produced mostly at night.…”

'The clocks that time us'—circadian rhythms in neurodegenerative disorders

“…The genetic underpinnings of circadian system disruption in AD are discussed in more detail elsewhere. 36 Although AD pathology seems to affect the pineal gland only to a limited degree, 37 melatonin secretion is disrupted and the diurnal pattern in the expression of the clock genes ARNTL, PER1 and CRY1 is lost in the pineal gland of patients with AD. 38 The periodic fluctuations in the expression of several clock genes are preserved in brain regions outside the SCN in patients with AD, 39 but abnormalities have been found in both the phase of the clock gene rhythms and the phase relationships between brain regions.…”