Sleep and its regulation: An emerging pathogenic and treatment frontier in Alzheimer's disease

Abstract

A majority of patients with Alzheimer's disease (AD) experience some form of sleep disruption, including nocturnal sleep fragmentation, increased daytime napping, decreased slow-wave sleep (SWS, stage N3), and decreased rapid-eye-movement sleep (REM). Clinical studies are investigating whether such sleep disturbances are a consequence of the underlying disease, and whether they also contribute to the clinical and pathological manifestations of AD. Emerging research has provided a direct link between several of these sleep disruptions and AD pathophysiology, suggesting that treating sleep disorders in this population may target basic mechanisms of the disease. Here, we provide a comprehensive review of sleep disturbances associated with the spectrum of AD, ranging from the preclinical stages through dementia. We discuss how sleep interacts with AD pathophysiology and, critically, whether sleep impairments can be targeted to modify the disease course in a subgroup of affected AD patients. Ultimately, larger studies that fully utilize new diagnostic and experimental tools will be required to better define the most relevant sleep disturbance to target in AD, the interventions that best modulate this target symptom, and whether successful early intervention can modify AD risk and prevent dementia.

Keywords: Alzheimer’s disease; Circadian rhythms; Dementia; EEG; Power spectra; Sleep.

Figure 1.. Hypothesized link between sleep disturbances and the progression of AD.

Sleep disturbances may be a risk factor that contributes to the accumulation of tau and amyloid during the earliest stages of the AD continuum and sleep disturbances may also present as a symptom in later disease stages.

Figure 2.

Hypothetical examples of circadian rhythms fit with cosinor regressions. The solid black represents a circadian rhythm from a healthy individual and the dotted line represents a circadian rhythm from an individual with Alzheimer’s disease. The period (peak to peak or trough to trough) is 24h. The amplitude is the difference between the peak (or trough) and the mean value of the cosine wave. The phase/acrophase refers to the timing of a reference point in the cycle (e.g., the peak) relative to time. In this example, the phase of the peak in the healthy individual occurs at ~18h, whereas the phase of the peak in the individual with Alzheimer’s disease occurs later (delayed) at ~21h.

Figure 3.

Sagittal brain section illustrating AD-related tau progression throughout the brain with key sleep-wake brain regions identified. The dark grey shading and black arrows indicate the spread of tau tangles from (A) locus coeruleus (LC) and other brainstem nuclei to (B) projections to the cerebral cortex and then (C) widespread cortical pathology. The size of the arrows indicates the progression, with the smallest arrows associated with the onset of tau accumulation in the brainstem and the larger arrows indicating the accumulation in the cortex later in the disease course. Figure 3 is based on the work of (Braak et al., 2011), image adapted from Wikimedia commons (Patrick J. Lynch, medical illustrator / CC BY).