At the Alzheimer’s Association International Conference 2017 held in London July 16-20, the relationship between disturbed sleep and AD came into sharper focus. Scientists revealed how sleep-disordered breathing boosts the risk for cognitive impairment. They also implicated disturbances in specific phases of sleep as risk factors for Aβ pathology and dementia. They pinpointed regions in the brain most affected by this sleep/neuropathology axis and shed light on molecular mechanisms that likely support it. Treating sleep disorders more widely may substantially reduce cognitive decline, and even AD, said scientists at the meeting.

People with sleep-disordered breathing (SDB) experience episodes of abnormally slow or shallow breathing (hypopnea) during sleep, or brief periods of no breathing at all (apnea). Several studies have reported a link between SDB and cognitive impairment in the elderly, but the results have been inconsistent. To better understand this relationship, Yue Leng, working in Kristine Yaffe’s lab at the University of California in San Francisco, sifted through a massive dataset. She pooled results from eight cross-sectional and six longitudinal studies, which together had medical data, including records of sleep patterns and cognition, on more than 4 million people. She selected those studies because each included at least 200 individuals who were older than 40, had used a standard apnea-hypoapnea index or a clinical diagnosis to ascertain SDB, and had assessed cognitive function using standard tests. To account for the different cognitive tests, SDB diagnostic methods, and populations recruited in each investigation, Leng and colleagues used statistical modeling to normalize the data.

Timing is Everything

Driven by sleep (black) and arousal (blue) circadian rhythms, production and clearance of Aβ in the parenchyma can complicate interpretation of its levels in the CSF (red). See below. [Image courtesy Cedernaes et al., 2017]

Analyses of the eight cross-sectional studies revealed that people with SDB had normal global cognitive function and memory, but slightly worse executive function. Might this increase risk for dementia? Data from the six longitudinal surveys suggested yes. From the records of more than 200,000 people, the researchers found that over three-15 years of follow-up, the roughly 11,000 people with SDB were 26 percent more likely to develop mild cognitive impairment (MCI) or dementia than were those who slept soundly. Given well-established interventions to treat SDB, such as continuous positive airway pressure devices and dental appliances, Leng and Yaffe emphasized the importance of improving SDB diagnosis and setting up studies to determine if these treatments can delay cognitive impairment. “It’s quite convincing that there’s a causal link. SDB could be a really important modifiable risk factor,” said Yaffe.

Disordered breathing conditions are quite common, affecting 13 percent of men and 6 percent of women aged 30-70 (Peppard et al., 2013). Obstructive sleep apnea (OSA), caused by partial or complete closing of the upper airway, strikes 9-24 percent of men and 4-9 percent of women aged 30-60. Obesity nearly doubles the risk (Romero-Corral et al., 2010). Also, the prevalence rises sharply with age, increasing two- to threefold in people over 65 (e.g., Young et al., 2002).

To investigate how OSA might increase risk for dementia, researchers led by Omonigho Bubu at Wheaton College in Illinois tested if it altered the rate of change of Aβ42, tau, and phosphorylated tau (p-tau) in the CSF, as well as Aβ burden in the brain, as assessed by positron emission tomography (PET) using the amyloid marker florbetapir. They obtained the data from the Alzheimer’s Disease Neuroimaging Initiative study (ADNI) database and included 1,639 individuals with an average age of 72-75 years who had reported as being either OSA-positive or OSA-negative. Of these, 516 were cognitively healthy, 798 had mild cognitive impairment (MCI), and 325 had been diagnosed with AD.

The researchers found that over approximately 2.5 years, Aβ built up more rapidly in the brains of OSA-positive individuals than in OSA-negatives, while Aβ42 levels dropped and tau and p-tau levels rose in the CSF. Interestingly, these associations emerged in the cognitively healthy and MCI groups, but not the AD group. “OSA might act as a modulator, accelerating amyloid deposition in those at risk for AD,” said Bubu. He cautioned that the sample size was small and that ceiling and floor effects may have limited biomarker changes in the AD group, since they already have substantial biomarker signals.

Other groups drilled down into the what, where, and how of sleep’s effects on dementia. In London, David Holtzman of Washington University in St. Louis showed how disrupting a particular stage of sleep called slow-wave sleep (SWS) promotes the buildup of Aβ in the CSF in healthy volunteers. During SWS, also known as deep sleep because it is harder to awaken from, the brain spends over 20 percent of its time generating slow (0.5 to 4.0 Hz), synchronized oscillations that can be recorded by electroencephalography (EEG). This slow-wave activity (SWA) contrasts with that during wakefulness and during rapid eye movement (REM) sleep, when electrical oscillations are mostly fast and desynchronized.

Holtzman and colleagues previously reported that in mice, neuronal activity, which drops during SWS, caused the release of soluble Aβ into the interstitial space. Others have found, in people, that clearance of Aβ from the brain accelerates during SWS (Oct 2013 news). In keeping with this, Holtzman and others found that in cross-sectional studies of healthy middle-aged and older people, stronger SWA correlated with lower CSF Aβ40 (Ju et al., 2016Varga et al., 2016).

To more definitively prove that SWA modulates Aβ, Yo-El Ju at WashU and Sharon Ooms at Radboud University in Nijmegen, Netherlands, monitored CSF Aβ levels in 17 healthy volunteers, aged 35-65, who were prevented from slipping into SWS. Right before bed, the researchers hooked up the volunteers to an EEG recorder to capture snapshots of their brain waves every 10 seconds, and fitted them with earphones. As soon as the tell-tale slow waves of SWS surfaced in the EEG, some participants heard a tone through the earphones that increased in volume until their slow waves subsided, indicating they were no longer in SWS. Others were allowed to sleep at will. The following morning between 9:30 and 10 am, the scientists collected CSF from the volunteers, and measured Aβ40 levels. As expected, for the most part, the volunteers who missed SWS the night before had higher levels of CSF Aβ than did controls. Also, the weaker the SWA, the greater the increases in CSF Aβ40. Why did CSF Aβ increase when its clearance from the parenchyma would be expected to decrease if sleep is disrupted? This may be because they measured close to the nadir of the daily CSF Aβ rhythm (9:30-10 a.m.). If SWS disturbance increased neural activity and delayed clearance, the nadir would come at a later time, and CSF Aβ at 9:30-10 a.m. be higher than in control groups (see figure above).

Interestingly, levels of no other protein the scientists measured in the CSF, including tau, changed in these overnight experiments, suggesting that Aβ production and clearance mechanisms are specifically related to sleep. However, when sleep disruptions occurred over a longer time, CSF tau rose as well. Ju and Ooms found that volunteers who slept poorly at home, as indicated by actigraphy wristbands that recorded how much they tossed and turned during six nights prior to CSF collection, had higher CSF tau levels. The findings appear in the Jul 10 Brain online (Ju et al., 2017).

“This is an important study and very nicely done,” said Barbara Bendlin of the University of Wisconsin in Madison. “It is consistent with prior work and shows a direct relationship between SWA and Aβ.”

In an accompanying commentary in Brain, Matthew Walker and colleagues from the University of California, Berkeley, noted the study extends the mostly correlational human studies to date (Mander et al., 2017). They cautioned, however, that the sample size is small and that other factors, such as the stress induced by the tones, changes in other sleep stages, or number of arousals, could contribute to the observed changes in CSF Aβ. Looking ahead, Walker and colleagues suggested questions for future studies: Which properties of SWS are critical for its effect on Aβ? Are slow waves produced in particular brain regions more likely to contribute to changes in Aβ or, conversely, more likely to be affected by AD pathology?

At AAIC, Kate Sprecher from Bendlin’s lab, addressed the last question. She described a preliminary study to probe the relationship between AD neuropathology and deficits in SWA in specific brain regions. The investigators recruited 19 middle-aged, cognitively healthy women and one man with a parental history of AD from the Wisconsin Alzheimer’s Disease Research Center. Their mean age was 57. The scientists measured CSF Aβ42 and t-tau, and monitored sleep with standard polysomnography, measuring global brain waves, blood oxygen levels, heart rate, breathing, as well as eye and leg movements overnight. They also recorded electrical activity in specific regions of the brain with high-density EEG using 256 electrodes. To measure amyloid burden in the brain, the scientists used florbetapir PET. The PET and EEG data were collected within days or weeks of each other, and CSF measurements were separated by a longer time interval. Unlike Holtzman’s study, Bendlin focused on chronic, rather than acute, levels of CSF Aβ and tau.

Sprecher looked for correlations between the t-tau/Aβ42 ratio and the power of the EEG recordings in the slow-wave range of 1-4.5 Hz across the cortex. The data revealed a strong link between CSF t-tau/Aβ42 and SWA specifically in the centro-parietal cortex: Higher CSF t-tau/Aβ42 levels correlated with reduced SWA in this area. And when they examined brain amyloid in the same volunteers using florbetapir PET, they found that reduced SWA significantly associated with greater amyloid burden in a subregion of the parietal lobe, the precuneus, which is affected very early in the course of AD pathology.

Might localized disruptions in SWA precede early AD neuropathology? Sprecher and Bendlin think so, but emphasize their study is preliminary. “We are collecting more EEG and PET data to extend these studies,” said Bendlin. Interestingly, obstructive sleep apnea also seems to correlate with disrupted SWA in posterior areas of the brain, including the precuneus, noted Sprecher (Jones et al., 2014). This could be a factor contributing to the observed links between OSA and dementia. An earlier study showed a correlation between amyloid deposition in the medial prefrontal cortex and fewer slow waves generated in this area during sleep in 75-year-old healthy controls (Jun 2015 news). Bendlin told Alzforum that she does not know how this relates to her findings, noting the work is preliminary and that the two studies had important differences, including the participants’ ages.

Making Brain Waves

Sleep spindles and K-complexes occur during a light sleep stage known as non-REM stage 2. Sleep spindles dwindle when tau rises in cerebrospinal fluid.

Others at AAIC claimed slow waves are not the only components of sleep linked to dementia. Ram Sharma, working with Ricardo Osorio at New York University School of Medicine, associated sleep spindles with biomarkers of tau pathology. These bursts of 10-16 Hz oscillations (see image above) appear mostly during non-REM stage 2 sleep, a stage of light sleep that accounts for about half of our sleeping time. Sharma suspected a connection between spindles and dementia because p-tau accumulates in the thalamus, where sleep spindles are generated. Others have reported fewer spindles per minute in AD and MCI (Gorgoni et al., 2016).

Sharma tracked sleep spindles by EEG and measured t-tau and p-tau in the CSF from 50 cognitively healthy adults aged 53 to 84. He found that shorter spindle duration ,as well as less dense spindles, correlated with higher levels of tau and even more tightly with p-tau. No correlations were found with Aβ42. Neither the spindles nor tau correlated with sleep quality, suggesting a poor night’s sleep cannot explain the correlation. Sprecher was intrigued by the findings. “The involvement of sleep spindles is really interesting,” she told Alzforum. “This is a very important wave form that plays a role in memory and cognition, but it has not been explored much in AD.” Holtzman’s group also found a relationship between tau and sleep in the P310S transgenic mouse, which expresses a mutant form of human tau. Jerrah Holth and colleagues found that decreased REM and non-REM sleep in these animals associated with an increase in tau pathology in the brainstem (Holth et al., 2017).

Additional evidence supporting a link between REM and dementia came from the studies of Matthew Pase of Swinburne University, Australia. While at Sudha Seshadri’s lab at Boston University, Pase found a link between this dream state and dementia in a subset of participants in the Framingham Heart Study Offspring cohort. The Offspring cohort is composed of more than 5,000 sons, daughters, and their spouses, of the original participants in the original Framingham Heart Study. Most of them were in their 20s-50s between 1971 and 1975, when the Offspring study started. The researchers pored over data from 321 cognitively healthy individuals who had gone through sleep assessments at a mean age of 67 using home-based polysomnography between 1995 and 1998. Pase then examined the incidence of dementia after a mean follow-up of 12 years. By then, 32 of the 321 had developed dementia, 24 due to AD. Pase was surprised to find that individuals who spent more time in REM during the night, and fell into REM sleep more quickly, had a reduced risk of all forms of dementia, including AD. Each percentage increase in REM sleep was associated with a 9 percent reduction in dementia risk. Interestingly, the team found no association between non-REM sleep and dementia risk. Although some studies have hinted at a link between REM and AD (e.g., Liguori et al., 2014), said Pase, most current observations point to a connection between SWS and dementia pathology. Pase offered a few hypotheses to explain his findings: a drop in REM may be a marker of a degenerating cholinergic system; REM might be curtailed by stress, which may also increase the risk of dementia; or a drop in REM could facilitate the development of dementia by reducing synaptic consolidation.

Molecular mechanisms to explain these multiple sleep-dementia connections are still lacking. However, researchers, including John Cirrito at WashU, are beginning to tackle the issue. Cirrito studies the signaling pathways that underlie the fluctuations in Aβ secretion that occur during the sleep-wake cycle. Previous studies had shown that more Aβ releases into the interstitial fluid (ISF) during wakefulness than during sleep. To delve into the molecular signaling that controls these fluctuations, Cirrito uses in vivo microdialysis to monitor Aβ levels in the ISF of living APP transgenic mice, while manipulating signaling cascades pharmacologically. At AAIC, he reported that inhibiting extracellular regulated kinase (ERK) increased ISF Aβ levels by 50 percent and blocked the sleep/wake fluctuation in ISF Aβ, suggesting ERK plays a role in the diurnal rhythm of Aβ production. Cirrito’s group found that orexin signaling, which normally promotes wakefulness, regulates the phosphorylation/activation of ERK, which in turn contributes to the diurnal fluctuations in ISF Aβ during the sleep-wake cycle. “It’s an interesting finding. It shows that ERK signaling is important in Aβ production and connects it with sleep,” said Holtzman.—Marina Chicurel

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References

News Citations

  1. From ApoE to Zzz’s—Does Sleep Quality Affect Dementia Risk?
  2. Does Amyloid Disturb the Slow Waves of Slumber—and Memory?

Research Models Citations

  1. Tau P301S (Line PS19)

Paper Citations

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  4. . Obstructive sleep apnea decreases central nervous system-derived proteins in the cerebrospinal fluid. Ann Neurol. 2016 Jul;80(1):154-9. Epub 2016 Jun 1 PubMed.
  5. . Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid Aβ42 Levels in Cognitively Normal Elderly. Sleep. 2016 Nov 1;39(11):2041-2048. PubMed.
  6. . Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain. 2017 Aug 1;140(8):2104-2111. PubMed.
  7. . A restless night makes for a rising tide of amyloid. Brain. 2017 Aug 1;140(8):2066-2069. PubMed.
  8. . Regional reductions in sleep electroencephalography power in obstructive sleep apnea: a high-density EEG study. Sleep. 2014 Feb 1;37(2):399-407. PubMed.
  9. . Parietal Fast Sleep Spindle Density Decrease in Alzheimer's Disease and Amnesic Mild Cognitive Impairment. Neural Plast. 2016;2016:8376108. Epub 2016 Mar 15 PubMed.
  10. . Altered sleep and EEG power in the P301S Tau transgenic mouse model. Ann Clin Transl Neurol. 2017 Mar;4(3):180-190. Epub 2017 Feb 15 PubMed.
  11. . Orexinergic system dysregulation, sleep impairment, and cognitive decline in Alzheimer disease. JAMA Neurol. 2014 Dec;71(12):1498-505. PubMed.

External Citations

  1. ADNI

Further Reading

No Available Further Reading