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.

Keywords: Alzheimer’s Disease; alpha-synuclein; sleep, amyloid; tau.

Fig. 1

Schematic of tau pathology in sleep, wake, and circadian brain regions and pathways. The ascending arousal system (blue) leading to cortical arousal is composed of brain regions active in wake (blue circles) or both wake and REM sleep (blue stars). Many of these regions are shown to be affected by abnormal tau pathology in pretangle stages, prior to cortical tau or Aβ pathology (pink outline) or in clinical AD (purple outline), suggesting a role for tau in sleep-wake dysregulation in aging and AD. The hypothalamic VLPO (orange square) sleep generating region inhibits wake active areas of the ascending arousal system (orange dash). However, the VLPO as well as the circadian master clock SCN (brown triangle) have not been shown to have significant tau pathology (no outline) in AD. The REM sleep producing SLD (green), which interacts with the REM-off ventrolateral PAG, and NREM/SWS generating PFZ (light purple) have not yet been studied for the presence of tau pathology (yellow outline) but could play a role in sleep loss seen in AD. Adapted by permission from Macmillan Publishers Ltd: Neuron (Saper et al., 2005).