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Review
. 2014;4(5):351-62.
doi: 10.2217/nmt.14.33.

The sleep-wake cycle and Alzheimer's disease: what do we know?

Miranda M Lim  1 , Jason R Gerstner, David M Holtzman
Affiliations
Review

The sleep-wake cycle and Alzheimer's disease: what do we know?

Miranda M Lim et al. Neurodegener Dis Manag. 2014.

Abstract

Sleep-wake disturbances are a highly prevalent and often disabling feature of Alzheimer's disease (AD). A cardinal feature of AD includes the formation of amyloid plaques, associated with the extracellular accumulation of the amyloid-β (Aβ) peptide. Evidence from animal and human studies suggests that Aβ pathology may disrupt the sleep-wake cycle, in that as Aβ accumulates, more sleep-wake fragmentation develops. Furthermore, recent research in animal and human studies suggests that the sleep-wake cycle itself may influence Alzheimer's disease onset and progression. Chronic sleep deprivation increases amyloid plaque deposition, and sleep extension results in fewer plaques in experimental models. In this review geared towards the practicing clinician, we discuss possible mechanisms underlying the reciprocal relationship between the sleep-wake cycle and AD pathology and behavior, and present current approaches to therapy for sleep disorders in AD.

Keywords: Alzheimer's; EEG; amyloid; amyloid-β; circadian; glia; hypocretin; orexin; sleep; wake.

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Figures

Figure 1
Figure 1. Schematic of possible mechanisms underlying the reciprocal relationship between sleep disturbances and Alzheimer’s pathology
In summary, sleep disturbances lead to increased waking neuronal activity-dependent Aβ and tau release, resulting in greater amyloid plaque and tau tangle deposition. Pathological proteins lead to neurometabolic uncoupling of lactate metabolism with the sleep–wake cycle, causing further sleep disturbances. Alzheimer’s disease pathology may also impact the immune system, continuing to feed forward alterations in sleep and subsequent pathology. Within the larger positive feedback cycle lies smaller positive cycles involving the default mode network, whose dysfunction exacerbates activity-dependent Aβ and tau, and impaired glia-lymphatic (‘glymphatic’) clearance of Aβ and tau, leading to increased Alzheimer’s disease pathology and astrocytic metabolic dysfunction. Aβ: Amyloid-β.
See this image and copyright information in PMC

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