Circadian Rhythm and Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with a growing epidemiological importance characterized by significant disease burden. Sleep-related pathological symptomatology often accompanies AD. The etiology and pathogenesis of disrupted circadian rhythm and AD share common factors, which also opens the perspective of viewing them as a mutually dependent process. This article focuses on the bi-directional relationship between these processes, discussing the pathophysiological links and clinical aspects. Common mechanisms linking both processes include neuroinflammation, neurodegeneration, and circadian rhythm desynchronization. Timely recognition of sleep-specific symptoms as components of AD could lead to an earlier and correct diagnosis with an opportunity of offering treatments at an earlier stage. Likewise, proper sleep hygiene and related treatments ought to be one of the priorities in the management of the patient population affected by AD. This narrative review brings a comprehensive approach to clearly demonstrate the underlying complexities linking AD and circadian rhythm disruption. Most clinical data are based on interventions including melatonin, but larger-scale research is still scarce. Following a pathophysiological reasoning backed by evidence gained from AD models, novel anti-inflammatory treatments and those targeting metabolic alterations in AD might prove useful for normalizing a disrupted circadian rhythm. By restoring it, benefits would be conferred for immunological, metabolic, and behavioral function in an affected individual. On the other hand, a balanced circadian rhythm should provide greater resilience to AD pathogenesis.

Keywords: Alzheimer’s disease; circadian rhythm; melatonin; pathophysiology; sleep.

Figure 1

Circadian rhythm regulates some of the key processes thought to be involved in Alzheimer’s disease etiopathogenesis and progression such as inflammation, cerebral blood flow, melatonin production, amyloid β clearance, glymphatic system and metabolism. Moreover, some of the events associated either with early pathobiological changes in Alzheimer’s disease, or late pathophysiological consequences are known as potential circadian disruptors. The most important AD-related circadian disrupting mechanisms include neurodegeneration of neurons and neural pathways critical for circadian signaling, insulin system dysregulation, oxidative stress, inflammation, and pathological homeostasis of Aβ and tau. Aβ—amyloid β.