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.

Role of Tau Protein in Remodeling of Circadian Neuronal Circuits and Sleep

“…These results are also in agreement with previous results obtained in tau KO mice (Cantero et al, 2010). Sleep alterations are observed as a function of normal aging, yet in AD, an exacerbated dysregulation of circadian sleep patterns increases in severity as the disease progresses, contributing to impairment in cognitive function (Musiek et al, 2015; Homolak et al, 2018).…”

Robust light–dark patterns and reduced amyloid load in an Alzheimer’s disease transgenic mouse model

“…Recent evidence from mouse and human studies suggests that disruption of circadian rhythms and fragmentation of daily sleep–wake cycles are not only a consequence of Alzheimer’s disease (AD) progression but may also drive disease pathology and precede symptom onset 1 – 4 . Sleep disruption is also one of the principal reasons for the institutionalization of persons with AD 5 .…”

Sirtuins, Mitochondria and the Melatonergic Pathway in Alzheimer&rsquo;s Disease<strong> </strong>

“…By releasing pro-inflammatory cytokines, required ongoing night-time inflammation suppresses pineal melatonin production, thereby forming the immune-pineal axis [69]. Heightened levels of immune-inflammatory activity and glia activation are core aspects of AD pathophysiology and will contribute to the circadian dysregulation associated with AD [70]. Inflammation-driven suppression of pineal melatonin will therefore attenuate melatonin's night-time suppression of immune and glia activation [71].…”