Could Sleep-related Conditions Be Included as Another Modifiable Risk Factor in Alzheimer’s Disease?

Sleep was not listed in the 12 modifiable risk factors in the Lancet Commission's report on dementia prevention published in 2020, which delays or prevents 40% of dementia.[1] The same report discussed sleep as a possible factor, but the previous studies on improving sleep quality to improve cognitive functions were inconclusive. Since this published report, new research findings have emerged, and evidence is growing that supports the idea that sleep is one of the critical factors contributing to the neurodegenerative disease process. Various components to assess the magnitude of the quality of sleep, including total sleep time, sleep latency, sleep efficiency, and percentages of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, have been studied. In particular, the proportion of slow-wave sleep, or stage 3 of the NREM phase, is gaining more attention. In light of this, it seems logical to examine the literature on the association of sleep with dementia and Alzheimer's disease (AD) as a reference, particularly since around and after the report was published in 2020. Thus, the purpose of this article was to review recent literature after the Lancet Commission's report to explore the association of sleep with AD. It is important to understand the term "modifiable risk factor" from the Lancet report. The report aimed to identify the possible factors that contribute to the disease process. These factors, unlike the REM behavior disorder in Lewy body disease, are not prodrome of the dementing illness. The report intended to help make policies at the community level, by which the so-called risk factors are made aware, so the community could make changes to behaviors accordingly. The authors have also discussed the likely mechanism by which modifying many of these risk factors could prevent dementia. REVIEWS ON SLEEP QUALITY A simple search using keywords as title words in the PubMed database was undertaken with time limits from 2020 onward. Three systematic reviews appeared suitable out of the 18 identified to appraise and discuss here.[2-4] All these three selected papers for discussion have followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, a standard guideline for systematic reviews, and therefore were included, and reviews were appraised. These three studies appear to add to the pool of evidence to make a case for sleep as an important risk factor that needs to be studied more. Zhang et al. reviewed the polysomnography (PSG)-based sleep studies in AD that included cross-sectional studies.[2] Objective assessment by PSG was the main strength of this study. They found that a reduced amount of slow-wave sleep and the REM phase of sleep significantly correlated with lower cognitive scores in persons with AD. This study also found an association with reduced sleep efficiency, total sleep time, increased REM latency, and frequent awakenings. This review is a good source of evidence to support the theory that sleep is linked to cognitive impairment and AD. Another systematic review by Casagrande et al. examined the association of sleep with mild cognitive impairment (MCI) in addition to AD, based on cross-sectional studies.[3] The review studied papers that had both subjective and objective measurements for sleep. The authors concluded that REM sleep, sleep efficiency, sleep latency, and sleep duration were affected in AD and MCI. The study finds evidence that the overall quality of sleep is associated with cognitive impairment. The latest systematic review by Wang et al. that included longitudinal studies found a significant association between self-reported sleep problems and the incidence of AD.[4] This association was not significant with objective measurements of sleep. Another important finding from this review was that both the shorter sleep duration and longer sleep duration appeared to be risk factors for AD.[4] Nevertheless, the study supports the evidence for the association of sleep with AD. REVIEW ON OBSTRUCTIVE SLEEP APNEA The above search also identified another article by Yeo et al., in 2023, that included cross-sectional and observational cohort studies aimed to find if there is any association between obstructive sleep apnea (OSA) and the markers of AD both in blood and cerebrospinal fluid (CSF).[5] The study found that the blood Aβ42 levels were high in the OSA group compared with healthy controls. In CSF, levels of Aβ42 were found to be low in OSA, which indicates brain deposition of Aβ amyloid protein. This systematic review supports the hypothesis that OSA is associated with AD. The report by the Lancet Commission appraised the available evidence related to sleep. Some reports indicated sleep disturbance was linked to reduced glymphatic clearance, low-grade inflammation, and cardiovascular disease all contributing to cognitive impairment.[1] It has been believed that there are sleep disturbances that promote the basic mechanism of AD with increased deposits of plaques and tangles. The above quality review papers since that report will add to the evidence base with regard to sleep disturbance in general. With this available evidence, now, future studies could focus on various components of sleep that need to be targeted to reduce the factors contributing to the disease process. COMPONENTS OF SLEEP QUALITY NREM stage 3, or deep sleep, also known as slow-wave sleep, has been studied in AD, and its disruptions are linked to AD pathology.[6] The authors proposed improving sleep quality by restoring slow-wave activity by therapeutic means could help in modifying the disease process. It has been proposed that the possible underlying mechanisms could be enhanced clearance of Aβ occurring in a phase of slow-wave sleep. The other possibility is the correlation between total sleep duration and Aβ42/40.[7] The glymphatic system of the brain is regulated mainly by sleep, and in particular, the slow-wave activity of the NREM stage.[8] Sleep disruptions lead to glymphatic drainage, and this mechanism may worsen the neurodegenerative process of AD. Himali et al. published their cohort study based on multiple objective PSG studies and found that each percentage decrease in slow-wave sleep will lead to an increase in the risk of dementia by 27%.[9] The authors here, as well as Zhang et al., in 2022, had put forth the same argument that sleep appears to be another modifiable risk factor in dementia, and improving this would reduce the chances of AD or delay in onset or progression, which the future studies need to look more longitudinally.[2] Studies point out that the quantity of slow-wave sleep could play a major role in the degenerative process or at least the association with AD in general.[9] Total sleep time, sleep efficiency, REM percentage, and REM latency could be related to the process. Contribution of confounding factors such as depression, diabetes, and hypertension may be taken into account. The link between OSA and degenerative processes needs a closer look in the presence of many possible confounding factors such as hypertension and obesity. A recent 10-year follow-up study showed that longer sleep duration in older people over 70 years of age is a risk factor and possibly an early warning indicator of neurodegenerative processes.[10] A U-shaped association, which means both a shorter and longer duration, can be risk factors. CONCERNS RELATED TO EVIDENCE The reviews based on cross-sectional or case–control kind of designs may not be adequate sources of evidence.[2,3,5] Another recent review although it included longitudinal studies, did not find evidence to suggest that sleep-related disturbance was contributing to the AD on objective assessment outcomes.[4] A shorter duration in middle age may be a risk factor for dementia.[11] Furthermore, sleep itself is a broader area, and studies examining different parameters cannot be generalized to sleep disturbance as a whole. There are 10 different types of sleep-related conditions being implicated.[12] Although the slow-wave sleep phase and OSA seem to be getting more focus, more evidence may be required for other specific parameters in sleep. Clinically, there are no proven disease-modifying agents available that could reverse the process of AD although a couple of new drugs have got US FDA approval in recent times, and further reports are awaited on their use. In this context, the prevention aspect plays a major role. Sleep is an understudied area in general that could be modified, and recent findings must inspire the research funding agencies to encourage scientists to work in this area. It is hoped that if sleep is found out to be risk factor for AD and it is improved at the community level, then this could reduce the burden of AD and its impact. CONCLUSION Since the last report, the evidence in terms of research interest looking at various aspects of sleep and AD is growing, suggesting the likelihood of it being recognised a potential modifiable risk factor. However, the issue is that several sleep-related conditions need a closer look and one has to be specific about which part of sleep is a risk factor that needs to be modified. Therefore, suggesting sleep as a whole as another modifiable risk factor may not be helpful. The Lancet Commission while considering revising to include sleep, must bear in mind to be more specific on which sleep conditions and how could one modify specifically to address that part of sleep. Quality of sleep must be assessed and necessary advice needs to be offered to improve overall sleep. In general, sleep hygiene must continue to be part of public health literacy programs.