State of the field
The accelerating pace of research on the link between sleep or circadian function and Alzheimer Disease (AD) has raised the possibility of targeting sleep or circadian behaviors to mitigate AD risk. Sleep and circadian functions are separate but intertwined, in that circadian mechanisms coordinate physiological functions to the 24-hour clock for optimal function, including sleep-wake state. Accumulating data support a bi-directional relationship between AD pathology and sleep-circadian function. Even during the 15+ year “preclinical” pre-symptomatic stage of AD, decreased sleep quality and fragmented circadian rhythms are associated with AD pathology.1,2 Conversely, sleep-circadian dysfunction, particularly slow-wave sleep disruption, elevates levels of amyloid-beta (Aβ) and tau.3–5 Large longitudinal studies show that obstructive sleep apnea and insufficient sleep increase risk of cognitive impairment.6,7 Given the high prevalence of sleep-circadian dysfunction—an estimated 1 billion individuals have OSA, and 40% in a large survey reported insufficient sleep7,8—sleep-circadian function may be a high-impact target for intervention as a modifiable AD risk factor.
Despite the clear clinical need for therapeutic strategies to address sleep-circadian dysfunction, at the bedside we are stymied by lack of screening tools, prognostic markers, and most importantly, treatments to offer patients. In mice, orexin (hypocretin) receptor antagonists mitigated amyloid plaque formation,4 and while these medications are FDA-approved for insomnia, there have been no trials examining the effects of these or any other sleep-circadian therapies on AD biomarkers and outcomes. Treatment with positive airway pressure (PAP) for OSA has shown only very modest effect on neurocognitive function in cognitively-normal or -impaired individuals.9,10 Otherwise, there is a wide gap between bench and bedside. Here, we provide recommendations for advancing and translating sleep-circadian science into new strategies for AD prevention and treatment.
Basic Research
Major basic science questions remain unanswered regarding the interactions between sleep and AD pathogenesis. Sleep deprivation increases amyloid and tau pathology in mice, but it remains uncertain if sleep alters brain production or clearance of Aβ and tau, or both.11–13 Sleep-circadian dysfunction may impact other pathways that contribute to AD, including neuroinflammation, proteostasis, and synaptic health, but exact mechanisms are unknown. It is also unclear which aspect of sleep, such as sleep duration, specific sleep stage(s), consolidation/timing of sleep, slow wave sleep, or other variables are most critical in AD pathogenesis. Understanding molecular mechanisms by which OSA contributes to AD might also facilitate molecular therapies which could be used in combination or in lieu of PAP. Finally, therapies directly targeting circadian functions require development and translation. Ideally, future therapies would directly target or augment sleep/circadian-mediated mechanisms, without necessarily inducing sleep.
Clinical Research
Clinical studies need to account for the bi-directional nature of AD pathology and sleep-circadian function, and the long preclinical stage of AD. To demonstrate a causal relationship between sleep-circadian dysfunction and AD, studies must either 1) assess sleep-circadian phenotypes 20+ years prior to cognitive symptom onset; or 2) detect preclinical AD using biomarkers in longitudinal studies that include sleep-circadian measures. One study reported that insufficient sleep during midlife increased risk of AD up to 25 years later, suggesting that sleep problems contribute to AD pathogenesis,7 otherwise, there are no published studies appropriately-designed to determine causality. Certainly, sleep-circadian measures should be added to existing longitudinal studies of aging and dementia, and studies should aim to enroll diverse cohorts, to asses for any racial/ethnic effects on the sleep-AD relationship.
Methods for sleep-circadian measurement require further development, validation, and consensus. A shift away from subjective questionnaires and toward objective measures is needed, though gold-standard methods such as polysomnography and dim light melatonin onset are cumbersome to implement. Actigraphy is an attractive option, as it is easy to deploy in larger populations and provides data on both sleep and circadian rhythms, though it does not directly measure either. Emerging technologies such as home electroencephalography, wearables, home OSA diagnosis, and “smart” devices hold great promise. However, all of these methods need thorough validation across diverse populations. Open and consistent data access, formats, and analysis methods are also needed to facilitate pooling and sharing of data across studies. The lack of biologically-based biomarkers for sleep-circadian functions hampers research by forcing reliance on direct measurement, and a critical need exists for development of such biomarkers, including transcriptomic and proteomic approaches. Finally, genetic approaches such as Mendelian Randomization have potential to identify causative genetic links between sleep and AD risk.
Clinical Trials and Implementation
While the therapeutic pipeline targeting sleep/circadian mechanisms is growing, such as orexin antagonists or slow-wave sleep enhancement, no human studies have examined the effect on AD-related biomarkers, disease risk, or progression of cognitive symptoms and functional status. For circadian disorders, melatonin (and its agonists) and light exposure are currently mainstays of therapy but have limited effect in symptomatic AD. Trials assessing the impact of these and other more traditional sleep-circadian therapies (such as CBT for insomnia or CPAP for OSA) on AD-related outcomes could be done immediately and have immense clinical impact. Sleep-circadian disturbance in dementia is extremely challenging to treat, particularly balancing effective treatment of insomnia without daytime sedation. The recent approval of suvorexant for insomnia in AD is a step forward, but further drug development in this area is needed.
Greater implementation efforts are required to take the emerging science on the sleep-circadian and AD relationship to benefit at the societal level. Hospitals and other institutions need to promote policies to promote sleep-circadian health, such as optimizing light exposure and limiting disturbances during sleep. For neurologists seeing patients with memory concerns, it is vital to assess for sleep hygiene habits (including use of antihistamines or alcohol for self-medication of insomnia) and OSA that may be contributory. The absence of effective screening measures for sleep-circadian dysfunction is a problem, and in parallel, educational messaging is needed to publicize a normal/optimal range for sleep behaviors: as consumer-targeted sleep wearables have gained traction, orthosomnia (an unhealthy preoccupation with sleep) has emerged as a new source of sleep disruption. Expert, evidence-based guidelines for sleep-circadian health behaviors, screening, treatment, and monitoring are needed, with attention to effectively communicating with the layperson, who will ultimately be responsible for their daily (or nightly) sleep practice.
Summary
A growing body of evidence supports the link between sleep-circadian function and AD risk. A “tsunami” of AD looms in the coming 20–30 years, and sleep-circadian therapies that reduce AD risk would monumentally benefit societal health. To achieve such a goal, researchers in this area must intentionally adopt strategies to translate science efficiently and collaboratively into clinical trials and public implementation.
Table 1:
Recommendations for sleep and circadian research aimed at the prevention or treatment of Alzheimer Disease (AD)
| No AD pathology | Preclinical (asymptomatic) AD | Symptomatic AD | |
|---|---|---|---|
| Basic research | Identify mechanisms linking sleep to Aβ/tau production/clearance | Examine effect of different sleep/circadian-promoting drugs or interventions on tau aggregation, inflammation, synaptic function, other degenerative processes in preclinical models. | |
|
| |||
| Clinical research | Longitudinal (20 + years) followup studies | AD biomarker assessment regardless of cognitive status | Test effect of existing treatments on cognitive outcomes, with specific attention to safety & tolerability |
| Objective measures of sleep and circadian function | Objective measures of sleep and circadian function | ||
| Analytic methods for non-linear risk factors (e.g. sleep time) | Assess for obstructive sleep apnea and other sleep disorders | Identify and test new non-sedating therapies for sleep-circadian disruption in dementia patients | |
| Assess for obstructive sleep apnea and other sleep disorders | Test effect of existing treatments (ex: PAP for OSA; medication for insomnia) on AD markers | ||
| Genetic, race/ethnicity | Genetic, race/ethnicity | ||
| Sleep-circadian biomarkers | |||
|
| |||
| Trials and implementation | Screening measures for abnormal sleep/circadian function | ||
| Tractable markers of abnormal sleep/circadian dysfunction | |||
| Determination of a goal range. | |||
| Education and outreach | |||
Acknowledgments:
ESM and YSJ both drafted and critically revised this manuscript. ESM and YSJ receive research funding from the National Institute on Aging (RF1AG061776) and from the Centene Corporation for work in sleep, circadian rhythms, and Alzheimer Disease. ESM has received research funding from Eisai Pharmaceuticals for work related to sleep and Alzheimer Disease. YSJ receives compensation for consultancy for Applied Cognition, a healthcare technology company. None of the listed entities had any role in the conception, writing, approval, or any aspect of this work.
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