Sleep Disturbance as a Potential Modifiable Risk Factor for Alzheimer's Disease

Abstract

Sleep disturbance is a common symptom in patients with various neurodegenerative diseases, including Alzheimer's disease (AD), and it can manifest in the early stages of the disease. Impaired sleep in patients with AD has been attributed to AD pathology that affects brain regions regulating the sleep⁻wake or circadian rhythm. However, recent epidemiological and experimental studies have demonstrated an association between impaired sleep and an increased risk of AD. These studies have led to the idea of a bidirectional relationship between AD and impaired sleep; in addition to the conventional concept that impaired sleep is a consequence of AD pathology, various evidence strongly suggests that impaired sleep is a risk factor for the initiation and progression of AD. Despite this recent progress, much remains to be elucidated in order to establish the benefit of therapeutic interventions against impaired sleep to prevent or alleviate the disease course of AD. In this review, we provide an overview of previous studies that have linked AD and sleep. We then highlight the studies that have tested the causal relationship between impaired sleep and AD and will discuss the molecular and cellular mechanisms underlying this link. We also propose future works that will aid the development of a novel disease-modifying therapy and prevention of AD via targeting impaired sleep through non-pharmacological and pharmacological interventions.

Keywords: Alzheimer’s disease; amyloid beta; cognitive behavioral therapy for insomnia; default-mode network; proteostasis; sleep disturbance; sleep fragmentation; slow-wave sleep; tau.

Figure 1

Bidirectional relationship between Alzheimer’s disease (AD) and impaired sleep. Impaired sleep is prevalent in patients with AD. Both epidemiological and experimental studies have led to the recent concept of a bidirectional relationship between AD and impaired sleep. In addition to the conventional concept that impaired sleep is a consequence of AD pathology affecting brain regions regulating the sleep–wake or circadian rhythm, impaired sleep has been suggested as a risk factor for the initiation and progression of AD.

Figure 2

Impaired sleep as a potential therapeutic target to restore proteostasis. Healthy proteostasis is maintained through the coordination of various intra- and extracellular systems that regulate protein synthesis, folding, disaggregation, and degradation (left). Increased synthesis of misfolded proteins, dysfunction of protein refolding or degradation systems, or changes in extracellular environment can lead to impaired proteostasis and result in the accumulation of misfolded and aggregation-prone toxic proteins (right), which is a common pathomechanism underlying neurodegenerative diseases. Based on recent studies that have indicated that impaired sleep leads to impaired proteostasis (middle; red arrow), future studies that better examine the relationship between sleep and proteostasis could lead to the development of novel therapeutics that restore healthy proteostasis via better quality of sleep (middle; blue arrow).