Alzheimer’s disease (AD), an age-related neurodegenerative disorder that affects millions of individuals worldwide, is not simply memory loss that can affect cognition, complex reasoning, and organised behaviour, to the extent that executing activities of daily living is compromised. AD has identified risk factors, notably age and genetic neurodegeneration, but recent work has pointed to sleep disturbances as additional risk factors in the recruitment and advancement of AD. The relation between sleep and AD is complicated and reciprocal, with growing evidence to support the theory that sleep impairments happen as a result of AD pathology and could play a large role in recruiting new types.
The Role of Sleep in AD Pathobiology
Alzheimer’s disease (AD) is characterised by the presence of amyloid-β (Aβ) plaques in the brain. Many studies have suggested that sleep disruption may contribute to the development of Aβ plaques and that healthy, restorative sleep may be related to low levels of Aβ. In animal models with Aβ deposition and sleep deprivation, researchers have found that Aβ levels correlate with a lack of sleep. Increased levels of Aβ negatively affected the sleep architecture, including increased wakefulness and disruptions to consolidated sleep. Interestingly enough, Aβ accumulation leads to increased sleep disruptions, which worsen alzheimer’s pathology. Early detection of these allows for early intervention and better management of the disease.
Interestingly, cognitively normal adults in the pre-clinical stages of AD, with amyloid plaques, frequently experience sleep disturbances. The sleep difficulties can even present before any apparent cognitive decline, highlighting the potential scientific and clinical significance of sleep disturbances as early indicators of AD pathology. Indicators of sleep disturbance include insomnia, sundowning behaviours (agitation and confusion increase late in the afternoon or evening), and increased daytime sleepiness. Sleep disturbances often correspond to the accretion of disease pathology. Individuals’ circadian slow waves decreased in amplitude with degeneration of early involved brain regions in AD, so declines in sleep may well coincide with disease progression.
In animal models such as a 5xFAD mice model of AD, disturbances in sleep-wake cycles become consistently worse with the accumulation of amyloid plaques. These disturbances are often exhibited at the time that amyloid and tau can be seen in the brain. The relationship between amyloid and sleep disturbances may also imply that sleep regulatory processes are influencing amyloid deposition in a way that complicates the relationships between sleep and AD even further.
The Mechanism: Tau, Aβ, and the Orexinergic System
Sleep disruptions in Alzheimer’s disease are not just related to amyloid-β, as tau accumulates in the brain of patients with AD and assumes a role in sleep disruptions. Recent studies of the underlying the molecular mechanisms of sleep disruption in AD show evidence that accumulation of Aβ and tau downregulates orexin A, which is a neuropeptide that regulates the sleep-wake cycle. In the model of orexin A signaling being overactive, the result is increased wakefulness and disrupted sleep.
In animal models (e.g. rats or mice) treated with Aβ, elevations in tau and phosphorylated tau (p-tau) and tau inhibitors reversed sleep-wake disturbances. Overall, these findings would suggest both amyloid-β and tau and the orexinergic system may be responsible for sleep-wake disturbances related to Alzheimer’s disease.
By ascertaining in what manner the proteins work together in sleep regulation, could lead to exploring additional therapeutic interventions that address sleep disturbances and other Alzheimer’s disease symptoms.
Sleep and Early Alzheimer’s Diagnostic Tool
Given the existence of sleep disorders that often occur early in the course of Alzheimer’s disease, there is increasing interest in examining sleep patterns as potential predictors of the disease. Recently, it was reported that the coupling of slow oscillation (SO) and sleep spindles (SS) during non-rapid eye movement (NREM) sleep might predict tau burden in the medial temporal lobe – an area of the brain quite affected very early in AD. Moreover, decreased amplitude of slow-wave activity (SWA) during sleep has been identified in Aβ burden.
Retrospective reports of changes in sleep duration and sleep quality over a lifetime were also found to predict late-life Aβ and tau burden, which implies that chronic disturbances in sleep could be an early indicator of the development of Alzheimer’s disease pathology. Overall, the quality of sleep may act as a non-invasive and cost-effective biomarker of early AD. Monitoring sleep patterns in older adults could offer valuable insights into the emergence of the disease and provide opportunities for intervention before cognitive decline becomes apparent.
The Importance of Sleep Duration in the Risk of Developing Alzheimer’s Disease
Epidemiological evidence indicates that short sleep duration and long sleep duration are positively associated with, and lead to, cognitive decline with dementia. In terms of sleep disordered breathing, this has now been established as a significant risk factor for incurring mild cognitive impairment or dementia as a result of excessive desaturation while asleep, indicating we need to have healthy patterns of sleep that will help mitigate the risk for Alzheimer’s.
More specifically, the sleep stage slow-wave sleep (SWS), the deepest level of non-REM sleep SWS is essential for brain clearing types of waste products, including Aβ, and is also recognised as an important part of brain health. During the SWS stage of sleep, there is reduced metabolic activity that is believed to help clear Aβ via the glymphatic pathway (i.e., fluxing from the interstitial fluid to the CSF with sleep). Therefore, if sleep patterns are disrupted during SWS and possibly do not allow for as much SWS or are fragmented, this would impair clearance and potentially lead to increased total amyloid deposition.
Therapeutic Implications: Sleep Interventions in Alzheimer’s Disease
Given the strong connection between sleep and Alzheimer’s disease, improving sleep problems may be a therapeutically beneficial intervention to avoid AD risk and slow down disease progression. Recent studies in animal models have demonstrated that a one-month sleep intervention that included sleep enhancement (e.g., orexin receptor antagonists) reduced Aβ deposition and preserved the normal sleep structure. Specifically, targeting the orexinergic system (orexins are involved in wakefulness) may provide a treatment for sleep disturbance in patients with AD.
In addition to pharmacological interventions, lifestyle changes such as maintaining a consistent sleep schedule, reducing environmental stressors, and addressing sleep-disordered breathing could offer valuable strategies for improving sleep quality and reducing AD risk.
Conclusion: The Future of Research on Sleep and Alzheimer’s Disease
The intersection of sleep research and Alzheimer’s research is an exciting opportunity. There is potential for early detection and intervention using sleep disturbance as a proxy for AD risk. Sleep disturbance is only one of many symptoms associated with AD, but if its precursor mechanisms are contributing to AD development via Aβ and tau accumulation, then they may hold a lot of promise as both an early biomarker for risk detection while potentially serving an early point of intervention to alter the course of risk ascribed to AD before overt cognitive decline begins.
The more we learn about the mechanisms connecting sleep to AD risk, we can highlight additional therapeutic targets within the sleep regulatory systems, and potentially within the orexinergic system. In the long run, promoting a lifetime of healthy sleep patterns may be critical to lower AD risk and slow its progression, providing an opportunity for those at risk and their families.
