Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease

Mar 22, 2016Sleep medicine reviews

Possible ways sleep-wake problems are linked to Alzheimer's disease

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Abstract

Disrupted sleep-wake cycles may accelerate the development and progression of Alzheimer's disease.

Extracellular levels of metabolites, including amyloid beta, increase during wakefulness.
Sleep aids in the clearance of these metabolites from the brain through fluid flow.
Disruption of the sleep-wake cycle is associated with reduced clearance of extracellular metabolites.
Increased levels of the wake-promoting neuropeptide orexin correlate with disrupted sleep patterns.
Disrupted sleep is linked to heightened neuronal oxidative stress and impaired blood-brain barrier function.
Alzheimer's disease-related changes can disrupt sleep and circadian rhythms even before clinical symptoms appear.

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During wakefulness, extracellular levels of metabolites in the brain increase. These include amyloid beta (Aβ), which contributes to the pathogenesis of Alzheimer's disease (AD). Counterbalancing their accumulation in the brain, sleep facilitates the removal of these metabolites from the extracellular space by convective flow of the interstitial fluid from the para-arterial to the para-venous space. However, when the sleep-wake cycle is disrupted (characterized by increased brain levels of the wake-promoting neuropeptide orexin and increased neural activity), the central nervous system (CNS) clearance of extracellular metabolites is diminished. Disruptions to the sleep-wake cycle have furthermore been linked to increased neuronal oxidative stress and impaired blood-brain barrier function - conditions that have also been proposed to play a role in the development and progression of AD. Notably, recent human and transgenic animal studies have demonstrated that AD-related pathophysiological processes that occur long before the clinical onset of AD, such as Aβ deposition in the brain, disrupt sleep and circadian rhythms. Collectively, as proposed in this review, these findings suggest the existence of a mechanistic interplay between AD pathogenesis and disrupted sleep-wake cycles, which is able to accelerate the development and progression of this disease.

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Candidate mechanisms underlying the association between sleep-wake disruptions and Alzheimer's disease

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