Sleep and dementia
Dementia, especially for people who have been caregivers or have lost loved ones to it, truly terrifies us—dementia slowly steals memories, personalities, understanding, and the essence of self. People tell me they fear dementia more than cancers, heart disease, stroke, accidents, or even death… it’s a powerful motivator to take action today to keep our brains healthy.
More and more research shows a link between sleep problems and dementia, and scientists (including myself) are working hard to sort out the mechanisms underlying this relationship. This is a very active area of research, and one near and dear to my heart. (In fact, this is my day job: the Barbara Burton and Reuben Morriss III Professorship was endowed by those donors to support research in Alzheimer’s Disease.) So, while this is a quick but deep dive into what we know so far about sleep and dementia, expect exciting updates in the near future.
First, a few definitions:
Dementia means a decline in cognitive functions, most commonly memory, to the point a person needs help with their activities of daily living.
Neurodegenerative disease: A progressive disease caused by dysfunction and death of a specific group of neurons. Different neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS, or Lou Gehrig’s disease) are caused by death of different populations of neurons.
The most common cause of dementia is Alzheimer’s disease (AD).
Brain changes in AD begin years prior to the earliest symptoms. When neurodegenerative changes have started but there are no symptoms, this is called the preclinical stage of AD.
Amyloid (also called amyloid-beta or beta-amyloid) and Tau are key proteins in AD. Clumping up of these proteins into amyloid plaques and tau tangles occurs during the preclinical stage of AD, and can be detected through various tests for about 20 years prior to AD symptoms.
Human research studies on sleep and dementia risk
Over the past two decades, a strong pattern linking sleep and dementia has emerged. The story begins with large studies of older adults: multiple studies have found that people with sleep problems were more likely to become cognitively impaired or diagnosed with dementia years later.
A large study of older women who were followed for close to 5 years found that having sleep apnea increased the odds of cognitive impairment or dementia by over 2x, after accounting for baseline function. (Yaffe et al., 2011)
In another community-based study, of older adults, those with the most disrupted sleep, as measured by an actigraph (wrist activity monitor) were about 1.5 times more likely to be diagnosed with AD over a 3-year followup. (Lim et al., 2013).
Moreover, even in the preclinical stage of AD, there is a relationship between poor sleep and AD.
In a study I did with the WashU AD Research Center participants, poor sleep quality measured by actigraphy increased the odds by 5-fold of having preclinical AD as measured by cerebrospinal fluid markers of amyloid plaques. (Ju et al. 2013)
In a follow-up study of the activity pattern over the 24-hour day, more fragmentation—meaning more activity at night and periods of inactivity during the day—was correlated with an AD-specific Tau/amyloid ratio. (Musiek et al. 2018)
Self-reported poor sleep quality was associated with a greater amount of amyloid plaques on brain PET scans. (Spira et al., 2013).
None of these studies were designed to show causality, ie whether sleep problems cause dementia, but they show a consistent association including at the earliest, preclinical, stages of disease. Notably, since we now know that sleep disturbances occur during the preclinical stage of disease, which can last ~20 years, we don’t know whether the initial longitudinal studies were due to reverse causation (ie whether early AD was leading to sleep problems).
More recently, a large (almost 8000 people) study with 25-year followup in the Whitehall cohort provided more evidence for a potential directional mechanism: those who slept 6 or fewer hours per night during mid-life (50’s and 60’s) had a 30% increase in dementia later in life, compared to those who slept 7+ hours. (Sabia et al., 2021).
Overall, multiple large human cohort studies support a strong link between sleep problems and AD. Likely, there is a bi-directional relationship between sleep problems and AD, but we need long-term studies with AD biomarker assessments from the beginning to fully address the question of direction.
Mechanistic studies in mice
Mouse experiments have filled the gap in understanding the mechanistic links between sleep disturbance and AD.
A landmark study from the lab of my mentor, David Holtzman, showed that amyloid increases during wake and decreases during sleep. Medications to sleep-deprive mice caused amyloid levels to be elevated, and chronic sleep disruption led to more amyloid plaques. (Kang et al., 2009).
More recently, the same lab showed that tau also increases with sleep deprivation. (Holth et al., 2019).
There is ongoing debate on why or how amyloid and tau levels increase with sleep disruption. One explanation is that these proteins are released by neurons during activity, so during sleep deprivation, relatively more is released compared to regular sleep. Another potential explanation is that the clearance of these proteins may be affected.
A clearance system—termed the “glymphatic” system—was described in another landmark paper (Xie et al., 2013). The glymphatic system ramped up during sleep, including clearance of amyloid that had been injected into the brain.
How sleep reduces amyloid and tau is important to pinpoint, because it is a potential target for medications to prevent neurodegenerative diseases. Whether it is production, clearance, or something else, this is a very active ongoing area of debate.
Translational studies: how does changing sleep in humans affect amyloid and tau?
Based on the mouse studies, several scientific groups have translated them back into humans, with particular focus on amyloid and tau.
Sleep deprivation increases cerebrospinal fluid levels of amyloid the next morning, in two separate studies, one by my WashU colleague Brendan Lucey (Lucey et al, 2018), and another by a group in the Netherlands (Ooms et al, 2014). A third study using amyloid PET showed similar results (Shokri-Kojori et al, 2018).
My lab did a study of selectively disrupting slow-wave sleep, which is deep non-REM sleep. Compared to a regular night of sleep, cerebrospinal fluid levels of amyloid were higher the next morning after disruption slow-wave sleep.
Lower slow wave sleep is associated with tau pathology in early and preclinical AD in a large cohort. (Lucey et al, 2019)
What we do not yet know is whether long-term sleep disruption in humans leads to more amyloid plaques, tau tangles, or dementia. After all, we can’t randomize people to different groups to get different amounts of sleep! Overall, these short-term studies support the mechanisms identified in mice, but do not prove that chronic sleep problems can cause AD in humans.
Schematic of the mechanistic links between sleep problems and Alzheimer’s Disease.
Active areas of research in sleep and AD
A major question is the chicken-and-egg one: do sleep disturbances lead to AD, or do AD changes such as amyloid plaques lead to sleep disturbances? Now that we have research cohorts with AD biomarkers (so we know who has preclinical AD or not) that have been followed for a decade, we can finally answer this question very soon!
Another critical question is if medications or other interventions to promote sleep can affect AD processes. There are multiple ongoing clinical trials of sleep medications and interventions at various stages of AD, or assessing effects on AD biomarkers (visit clinicaltrials.gov to search), but we certainly need more research along these lines to make a critical impact.
Sex effects: Both AD and sleep disturbances are both more common in women than men. We need more research on how sex affects the relationship of sleep and AD, and if/how hormone replacement can be optimized to reduce dementia risk.
We also know that having amyloid plaques decreases slow wave sleep and AD leads to damage to brain areas and circuits important for sleep. Research is ongoing on how to mitigate the impact of any existing AD on sleep, to break the feedback loop between sleep problems and AD.
Takeaways
Sleep disturbances increase risk of dementia, and Alzheimer’s disease in particular.
Deep slow wave sleep is important in modulating levels of amyloid and tau. Sleep disruption increases levels of amyloid and tau, key players in Alzheimer’s disease neurodegeneration.
Sleep problems are detectable even in preclinical AD, prior to any memory symptoms.
We do not know for sure *yet* if improving sleep during mid-life will reduce dementia risk years later. But the animal studies, human biomarker studies, and large long-term cohort studies altogether support sleep as a plausible and modifiable risk factor for AD. Also, getting better sleep certainly won’t hurt, and we will have the benefit of feeling well and enjoying the best quality of life while we are young. So for your best brain health, now and in the future, get the best sleep you can, tonight and every night!
References (alphabetical)
Holth JK, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363(6429):880-884. doi: 10.1126/science.aav2546. PMID: 30679382; PMCID: PMC6410369. Full text.
Ju Y, et al. Sleep quality and preclinical Alzheimer disease. JAMA Neurol. 2013;70(5):587-93. doi: 10.1001/jamaneurol.2013.2334. PMID: 23479184; PMCID: PMC3676720. Full text link.
Ju Y, et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain. 2017;140(8):2104-2111. doi: 10.1093/brain/awx148. PMID: 28899014; PMCID: PMC5790144. Full text.
Kang JE, et al. Science. 2009;326(5955):1005-7. doi: 10.1126/science.1180962. PMID: 19779148; PMCID: PMC2789838. Full text.
Lim AS, et al. Sleep Fragmentation and the Risk of Incident Alzheimer's Disease and Cognitive Decline in Older Persons. Sleep. 2013;36(7):1027-1032. doi: 10.5665/sleep.2802. PMID: 23814339; PMCID: PMC3669060. Full Text.
Lucey BP,e t al. Effect of sleep on overnight cerebrospinal fluid amyloid β kinetics. Ann Neurol. 2018;83(1):197-204. doi: 10.1002/ana.25117. PMID: 29220873; PMCID: PMC5876097. Full text.
Lucey BP. Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer's disease. Sci Transl Med. 2019;11(474):eaau6550. doi: 10.1126/scitranslmed.aau6550. Full text.
Musiek ES, et al. Circadian Rest-Activity Pattern Changes in Aging and Preclinical Alzheimer Disease. JAMA Neurol. 2018;75(5):582-590. doi: 10.1001/jamaneurol.2017.4719. PubMed PMID: 29379963; PubMed Central PMCID: PMC5885197. Full text.
Ooms S, et al. Effect of 1 night of total sleep deprivation on cerebrospinal fluid β-amyloid 42 in healthy middle-aged men: a randomized clinical trial. JAMA Neurol. 2014;71(8):971-7. doi: 10.1001/jamaneurol.2014.1173. PMID: 24887018. Full text.
Sabia S., et al. Association of sleep duration in middle and old age with incidence of dementia. Nat Commun.2021;12:2289. https://doi.org/10.1038/s41467-021-22354-2. Full text.
Shokri-Kojori M et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. PNAS. 2018;115 (17) 4483-4488. https://doi.org/10.1073/pnas.1721694115. Full text.
Spira AP, et al. Self-reported sleep and β-amyloid deposition in community-dwelling older adults. JAMA Neurol. 2013 Dec;70(12):1537-43. doi: 10.1001/jamaneurol.2013.4258. PMID: 24145859; PMCID: PMC3918480. PMC
Xie L. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-7. doi: 10.1126/science.1241224. PMID: 24136970; PMCID: PMC3880190. Full text.
Yaffe K, et al. Sleep-Disordered Breathing, Hypoxia, and Risk of Mild Cognitive Impairment and Dementia in Older Women. JAMA. 2011;306(6):613–619. doi:10.1001/jama.2011.1115. Full text.
