Sleep in Alzheimer's Disease–Beyond Amyloid

Abstract

Sleep disorders are prevalent in Alzheimer’s disease (AD) and a major cause of institutionalization. Like AD pathology, sleep abnormalities can appear years before cognitive decline and may be predictive of dementia. A bidirectional relationship between sleep and amyloid β (Aβ) has been well established with disturbed sleep and increased wakefulness leading to increased Aβ production and decreased Aβ clearance; whereas Aβ deposition is associated with increased wakefulness and sleep disturbances. Aβ fluctuates with the sleep wake cycle and is higher during wakefulness and lower during sleep. This fluctuation is lost with Aβ deposition, likely due to its sequestration into amyloid plaques. As such, Aβ is believed to play a significant role in the development of sleep disturbances in the preclinical and clinical phase of AD. In addition to Aβ, the influence of tau AD pathology is likely important to the sleep disturbances observed in AD. Abnormal tau is the earliest observable AD-like pathology in the brain with abnormal tau phosphorylation in many sleep regulating regions such as the locus coeruleus, dorsal raphe, tuberomammillary nucleus, parabrachial nucleus, and basal forebrain prior to the appearance of amyloid or cortical tau pathology. Furthermore, human tau mouse models exhibit AD-like sleep disturbances and sleep changes are very common in other tauopathies including frontotemporal dementia and progressive supranuclear palsy. Together these observations suggest that tau pathology can induce sleep disturbances and may play a large role in the sleep disruption seen in AD. To elucidate the relationship between sleep and AD it will be necessary to not only understand the role of amyloid but also tau and how these two pathologies, together with comorbid pathology such as alpha-synuclein, interact and affect sleep regulation in the brain.

Sleep and Human Aging

“…Interestingly, tau deposition is also present in other sleep-regulating areas such as the locus coeruleus and basal forebrain and can be observed even in cognitively normal older adults (Braak and Del Tredici, 2016; Braak et al, 2011; Stern and Naidoo, 2015). This leads to the currently untested hypothesis that tau within these regions may trigger sleep abnormalities years before degenerative disease onset and, if such sleep disruption is specific, could serve as an early diagnostic biomarker (Holth et al, 2016). It is additionally becoming clear that the link between degenerative dementia conditions and sleep disruption is bi-directional.…”

Mechanisms linking circadian clocks, sleep, and neurodegeneration

“…A wide variety of alterations in sleep have been described in human neurodegenerative diseases, including AD, PD, and HD, and are reviewed elsewhere(19, 20). In each of these diseases, sleep disturbances may precede the onset of more typical symptoms, in some cases by decades (3–5).…”

Polysomnographic assessment of suvorexant in patients with probable Alzheimer's disease dementia and insomnia: a randomized trial

“…Sleep disturbance and insomnia are common in Alzheimer's disease (AD), affecting ≈40% of patients . There is emerging evidence that poor sleep may contribute to the development of AD and impair memory function . Options for effective pharmacological treatment of insomnia in AD are limited, with inconsistent or poor‐quality evidence for efficacy of melatonin, second‐generation antipsychotics (which are primarily used to target other neuropsychiatric and behavioral symptoms associated with AD), and sedating antidepressants .…”