Scientists are beginning to probe the complex relationship between the brain changes involved in poor sleep and those in very early-stage Alzheimer’s. It’s an intriguing area of research, given that both risk for disturbed sleep and Alzheimer’s increase with age.

"Nearly 60 percent of older adults have some kind of chronic sleep disturbance,” said Phyllis Zee, Ph.D., a sleep expert at Northwestern University’s Feinberg School of Medicine, Chicago.

It’s long been known that people with Alzheimer’s often have sleep problems—getting their days and nights mixed up, for example. Now scientists are probing the link between sleep and Alzheimer’s earlier in the disease process and in cognitively normal adults. They wonder if improving sleep with existing treatments might help memory and other cognitive functions—and perhaps delay or prevent Alzheimer’s.

Which comes first, poor sleep or Alzheimer’s?

The chicken-and-egg question is whether Alzheimer’s-related brain changes lead to poor sleep, or whether poor sleep somehow contributes to Alzheimer’s. Scientists believe the answer may be both.

"We’re gaining new insights, primarily in animal studies, about a possible bidirectional relationship between sleep and Alzheimer’s disease,” said Mack Mackiewicz, Ph.D., who oversees sleep research for NIA’s Division of Neuroscience. Findings show that brain activity induced by poor sleep may influence Alzheimer’s-related brain changes, which begin years before memory loss and other disease symptoms appear.

NIA-funded scientists are studying the biological underpinnings of this relationship in animals and humans to better understand how these changes occur. Although evidence points to certain sleep problems as a risk factor for Alzheimer’s, "it is not known whether improving sleep will reduce the likelihood of developing Alzheimer’s,” Dr. Mackiewicz said. He adds, "There is no scientific evidence that sleep medications or other sleep treatments will reduce risk for Alzheimer’s.”

Effects of good and bad sleep

At any age, getting a good night’s sleep serves a number of important functions for our bodies and brains. Although our bodies rest during sleep, our brains are active. The process is not totally understood, but researchers think that sleep might benefit the brain—and the whole body—by removing metabolic waste that accumulates in the brain during wakefulness. In addition, it has been shown that some memories are consolidated, moving from short-term to long-term storage during periods of deep sleep. Other sleep stages may also influence memory and memory consolidation, research shows.

Disturbed sleep—whether due to illness, pain, anxiety, depression, or a sleep disorder—can lead to trouble concentrating, remembering, and learning. A return to normal sleep patterns usually eases these problems. But in older people, disturbed sleep may have more dire and long-lasting consequences.

Scientists long believed that the initial buildup of the beta-amyloid protein in the brain, an early biological sign of Alzheimer’s, causes disturbed sleep, Dr. Mackiewicz said. Recently, though, evidence suggests the opposite may also occur—disturbed sleep in cognitively normal older adults contributes to the risk of cognitive decline and Alzheimer’s disease.

For example, in a study of older men free of dementia, poor sleep, including greater nighttime wakefulness, was associated with cognitive decline over a period of more than 3 years (Blackwell et al., 2014). Sleep was assessed through participants’ reports and a device worn on the wrist that tracks movements during sleep.

Sleep disorders such as sleep apnea may pose an even greater risk of cognitive impairment. In a 5-year study of older women, those with sleep-disordered breathing (SDB)—repeated arousals from sleep due to breathing disruptions, as happens in sleep apnea—had a nearly twofold increase in risk for mild cognitive impairment (a precursor to Alzheimer’s in some people) or dementia (Yaffe et al., 2011).

In addition, certain types of poor sleep seem to be associated with risk of cognitive impairment, according to Kristine Yaffe, M.D., of the University of California, San Francisco. These include hypoxia (low oxygen levels that can be caused by sleep disorders) and difficulty in falling or staying asleep.

What’s the connection between sleep and Alzheimer’s?

Evidence of a link between sleep and risk of Alzheimer’s has led to investigations to explain the brain activity that underlies this connection in humans. Some recent studies suggest that poor sleep contributes to abnormal levels of beta-amyloid protein in the brain, which in turn leads to the amyloid plaques found in the Alzheimer’s brain. These plaques might then affect sleep-related brain regions, further disrupting sleep.

Studies in laboratory animals show a direct link between sleep and Alzheimer’s disease. One study in mice, led by researchers at Washington University, St. Louis, showed that beta-amyloid levels naturally rose during wakefulness and fell during sleep (Kang et al., 2009). Mice deprived of sleep for 21 days showed significantly greater beta-amyloid plaques than those that slept normally. Increasing sleep had the opposite effect—it reduced the amyloid load.

A subsequent study, also by Washington University researchers, showed that when Alzheimer’s mice were treated with antibodies, beta-amyloid deposits decreased and sleep returned to normal (Roh et al., 2012). Mice that received a placebo saline solution continued to sleep poorly. The results suggest that sleep disruption could be a sign of Alzheimer’s disease beginning in the brain, but not necessarily its cause.

Studies in humans have also addressed the relationship between sleep and biomarkers of Alzheimer’s disease. One study found that in cognitively normal older adults, poor sleep quality (more time awake at night and more daytime naps) was associated with lower beta-amyloid levels in cerebrospinal fluid, a preclinical sign of Alzheimer’s. Another study, by researchers at NIA and Johns Hopkins University, Baltimore, found that healthy older adults who reported short sleep duration and poor sleep quality had more beta-amyloid in the brain than those without such sleep problems. 

Emerging insights—stay tuned

How exactly do poor sleep and Alzheimer’s influence each other? Research so far suggests a few possible mechanisms:

Orexin, a molecule that regulates wakefulness and other functions, has been found to affect beta-amyloid levels in mice.
Chronic hypoxia, insufficient oxygen in blood or tissue that is a feature of sleep apnea, increased the level of harmful beta-amyloid in brain tissue of mice.
Reduced slow-wave sleep leads to increased neuronal activity.

Other factors may also be involved. For example, it has been shown in laboratory animals that the glymphatic system, the brain’s waste removal system, removes beta-amyloid during sleep. A recent mouse study suggests that sleeping in different positions impacts waste removal from the brain (Lee et al., 2015). Sleeping on the side cleared beta-amyloid more efficiently than sleeping on the back or belly, researchers found. They pointed to the glymphatic system as a possible pathway for intervention.

Further biological and epidemiological studies and clinical trials should cast more light on the mechanisms behind the sleep-Alzheimer’s connection, and whether treating poor sleep might help delay or prevent cognitive decline in older adults.

"Sleep is something we can fix, and people with sleep problems should consult a doctor so that they can function at their best,” Dr. Mackiewicz said. As for Alzheimer’s, for now, he said, improving sleep is "not the same as preventing Alzheimer’s disease. Researchers are committed to a achieving a better understanding of this complex dynamic in hopes of making a difference in the lives of older adults.”

Studies to examine the value of a good night’s sleep in delaying or preventing Alzheimer’s disease are underway. The following clinical trials are currently recruiting volunteers:

Auditory Stimulation of Slow-Wave Sleep and Memory in Older Adults
Sleep-Disordered Breathing and Alzheimer's Disease Prevention (SNAP)

References

Blackwell T, et al. Associations of objectively and subjectively measured sleep quality with subsequent cognitive decline in older community-dwelling men: the MrOS sleep study. Sleep 2014;37:655-663.

Kang J-E et al. Amyloid-β dynamics are regulated by orexin and the sleep-wake cycle. Science 2009;326:1005-1007.

Lee H, et al. The effect of body posture on brain glympathic transport. Journal of Neuroscience 2015;35(31):11034-11044.

Roh JH, et al. Disruption of the sleep-wake cycle and diurnal fluctuation of β-amyloid in mice with Alzheimer’s disease pathology. Science Translational Medicine 2012;4:150ra122.

Spira AP, et al. Impact of sleep on the risk of cognitive decline and dementia. Current Opinion in Psychiatry 2014;27:478-483.

Yaffe K, et al. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. Journal of the American Medical Association 2011;306(6):613-619.

Ju YS, et al. Sleep and Alzheimer’s disease pathology—a bidirectional relationship. Nature Reviews Neurology 2014;10(2):115-119.

For more information visit: https://www.nia.nih.gov/

~ Carolyn Van Dorn
3/7/2016