Elsevier

Ageing Research Reviews

Volume 12, Issue 1, January 2013, Pages 188-200
Ageing Research Reviews

Review
Reciprocal interactions between sleep, circadian rhythms and Alzheimer's disease: Focus on the role of hypocretin and melatonin

https://doi.org/10.1016/j.arr.2012.04.003Get rights and content

Abstract

AD, sleep and circadian rhythm physiology display an intricate relationship. On the one hand, AD pathology leads to sleep and circadian disturbances, with a clear negative influence on quality of life. On the other hand, there is increasing evidence that both sleep and circadian regulating systems exert an influence on AD pathology. In this review we describe the impairments of both sleep regulating systems and circadian rhythms in AD and their link to clinical symptoms, as this may increase knowledge on appropriate diagnosis and adequate treatment of sleep problems in AD. Furthermore we discuss how sleep regulating systems, and especially neurotransmitters such as melatonin and hypocretin, may affect AD pathophysiology, as this may provide a role for lack of sleep and circadian rhythm deterioration in the onset of AD.

Highlights

► AD pathology leads to sleep disturbances and circadian disruptions. ► Sleep disturbances have a negative influence on the quality of life of patients and care givers. ► Sleep deprivation and hypocretin increase levels and plaque deposition. ► Melatonin has anti-amyloidgenic properties. ► Important role of both melatonin and hypocretin in modulating AD pathophysiology.

Introduction

Alzheimer's disease (AD) is a neurodegenerative disorder expected to evolve into a disastrous worldwide epidemic within the next 40 years, unless treatment options delaying or curing the disease are found (Brookmeyer et al., 2007). Epidemiological studies have discovered many potential risk factors for AD, including modifiable life style factors, and still more risk factors are being discovered (Ballard et al., 2011). There is growing evidence that one of these factors is sleep. Clinical AD is often complicated by both circadian rhythm disruptions and sleep disturbances, which have a major impact on the quality of life of patients and their caregivers (Bianchetti et al., 1995, Pollak and Perlick, 1991). Interestingly, circadian and sleep disorders may in turn have a causal role in the pathophysiology of AD. Remarkable new data points to a link between hypocretin, a sleep-related neurotransmitter, and the amyloid β protein (Aβ), the protein accumulating in senile plaques in AD (Kang et al., 2009). A similar relation has been demonstrated for the circadian rhythm regulating hormone melatonin, and AD pathophysiology (Wang and Wang, 2006).

In this review we describe the current knowledge on the – possibly reciprocal – interactions between sleep and circadian disturbances and AD. After a description of the physiology of sleep and circadian regulatory systems, we discuss the impairments of these systems in clinical AD and provide a clinical overview on diagnosis and treatment of homeostatic sleep disorders in AD. Finally, we discuss the possible link between sleep and circadian rhythms and the onset of AD.

Section snippets

Sleep regulating systems

Sleep is a complex physiological state characterized by reduced or absent consciousness, relatively suspended sensory activity, and inactivity of nearly all voluntary muscles. The purpose and mechanisms of sleep are only partially clear and are subject of intense research (Siegel, 2009). Sleep and wakefulness are regulated by an intricate network of several separate brain mechanisms. The main ‘building blocks’ are 2 pathways, generating sleep and wakefulness respectively (Fig. 1). The brain

Impaired sleep regulating systems

Several anatomical elements of the AAS are affected in AD, including the nucleus basalis of Meynert in the basal forebrain, the thalamus, and several nuclei in the brainstem; the locus coeruleus, the upper raphe nuclei, and the tegmentopontine reticular nuclei (Braak and Braak, 1991b). The thalamus itself, which is thought to be involved in arousal, is severely affected in AD as well; neurofibrillary changes occur in the anteroventral nucleus of the thalamus and, to a lesser extent, in the

A causal role for sleep mechanisms in AD pathophysiology?

So far, we have described pathophysiological evidence of impairments in sleep regulating systems, caused by AD pathology. Interestingly, there are also indications for a reciprocal relationship: several studies have shown an influence of sleep and circadian related mechanisms on Aβ dynamics, impairments and even AD pathology.

Alzheimer's disease

Clinically, AD is primarily manifested by progressive memory loss, initially particularly memory for recent rather than remote episodes, and a gradual decline in global cognitive function interfering with the functions of daily living. Eventually the disease leads to death of the individual 3–9 years after diagnosis (Querfurth and LaFerla, 2010).

Neuropathologically, AD is characterized by a dramatic loss of neurons and synapses, especially in the hippocampus and cortex, with secondary

Discussion

AD, sleep and circadian rhythm physiology display an intricate relationship. On the one hand, AD pathology leads to sleep and circadian disturbances, with a clear negative influence on quality of life. On the other hand, there is increasing evidence that both sleep and circadian regulating systems exert an influence on AD pathology.

Acknowledgements

This work was funded by a grant from Alzheimer Nederland.

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