Amyloid-β can build up in the brain after just one sleepless night. So say researchers led by Nora Volkow at the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland. Using positron emission tomography, they found higher binding of the amyloid ligand florbetaben in the right hippocampi and right thalami of a small group of volunteers who were deprived of sleep for 31 hours. Other researchers were skeptical that insoluble Aβ would accumulate so rapidly. Volkow and colleagues also found that people who reported sleeping fewer hours at night tended to have more Aβ in those same areas, as well as in the nearby precuneus, which harbors plaques very early on in Alzheimer’s disease. The results appear in the April 9 Proceedings of the National Academy of Sciences.

“It is an intriguing study, but there are still lots of unknowns,” said John Cirrito, Washington University, St. Louis. It is unclear what the PET scan detected since the ligand, 18F-florbetaben, is reported to mainly bind plaques, not soluble Aβ, he said. Cirrito thinks it unlikely that detectable amyloid could accumulate in a single night. Other researchers expressed similar concerns.

Aβ in Sleepless Brain? In the right hippocampus (green) and right thalamus (red, left) more florbetaben binds (right) when people don’t sleep for one night (SD) than when they are in rested wakefulness (RW). [Courtesy of Shokri-Kojori et al., PNAS, 2018.]

Previous studies reported that soluble Aβ levels ramped up in the cerebrospinal fluid (CSF) when people spent a night without sleep, or when their deep sleep was interrupted (Jun 2014 news; Ju et al., 2017; Sprecher et al., 2017). One recent report suggested that faster Aβ production during sleep deprivation contributed to the uptick (Jan 2018 news). “However, changes in the CSF don’t always reflect changes in the brain. To really understand the dynamics of Aβ you have to look in the brain itself,” said first author Ehsan Shokri-Kojori.

The researchers used the PET tracer 18F-florbetaben to detect Aβ in the brains of 20 healthy people between ages 22 and 72. The volunteers spent two separate nights at a clinic: During one they got a good night’s sleep, while during the other, two weeks later, they were kept awake. In each case, they had a PET scan early the next afternoon. The researchers used the cerebellum as a reference region to calculate florbetaben standard uptake value ratios (SUVRs) 90–110 minutes after tracer infusion.

In 19 volunteers, small regions in the right side of the brain, including the hippocampus and thalamus, bound more PET tracer after their sleepless night than after the night of slumber (image above). The size of the SUVR increase, on average 5 percent, is consistent with increases in soluble Aβ found in the interstitial fluid of mice brains after sleep deprivation (Sep 2009 news). 

The researchers also found that volunteers who reported the fewest hours of sleep generally, outside of this experiment, had higher florbetaben signals, which extended more widely across the brain to include the bilateral putamen, the parahippocampus, and the right precuneus. Interestingly, in a recent study, older healthy people who were sleepier during the day also accumulated Aβ in the precuneus and in the nearby cingulate cortex (Mar 2018 news). 

Henrik Zetterberg, University of Gothenburg, Sweden, said it will be important to look for confounders, such as changes in blood flow due to sleep deprivation, which can affect the florbetaben signal. “I don’t think a person who stays up for one night wakes up with Aβ plaques the next day,” he said. The authors tried to minimize effects of both blood flow and tracer clearance using different PET analyses, including florbetaben-binding potential (Bullich et al., 2017). This dynamic measure tracks tracer binding continually and is thought to be more accurate and less sensitive to perfusion effects than SUVR measures. Binding potentials were also higher after sleep deprivation. The authors noted that the signals they see may derive, at least in small part, from soluble forms of Aβ, rather than plaques (Ni et al., 2013Yamin et al., 2017). 

Still, William Klunk, University of Pittsburgh, remained skeptical. “Even if these findings could be reproduced by an independent group with another amyloid tracer, I would still wonder if the sleep deprivation had a systematic impact on tracer kinetics rather than on Aβ deposition itself,” he wrote in an email to Alzforum.

Zetterberg’s group recently reported that Aβ levels remained unchanged in the CSF when sleep was restricted to a maximum of four hours per night during five consecutive nights, without any daytime naps (Olsson et al., 2018). “Most of us sleep at least four or five hours a night, which might not be so harmful,” he said.—Marina Chicurel


  1. This is an interesting study, presenting findings in line with our earlier work showing that a single night of sleep deprivation affects cerebrospinal fluid levels of Aβ (Ooms et al., 2014) and with recent work by Yu et al. (2017) indicating that slow-wave sleep disruption (and not full sleep deprivation) alone already affects CSF Aβ (Ooms et al., 2014). A likely mechanism for these changes in amyloid levels is increased amyloid production during wakefulness (or reduced production during sleep) as was recently demonstrated by Lucey et al. (2018)

    I am a bit skeptical, however, about the present study's findings using PET-amyloid imaging. Previous work on sample size calculations to detect relevant changes in amyloid concentrations using PET-amyloid imaging (Su et al., 2016) concluded that large sample sizes are required ( > n=200 per group). I would not a priori have considered using PET-amyloid imaging in this design with n=20. In the article I missed a thorough discussion on this aspect. The same holds for the question whether it is really Aβ binding we are looking at, or, for example, differences in perfusion, and would like to hear comments from experts in nuclear medicine on these findings.


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  2. This is a very interesting paper. The authors report increased Aβ deposition on PET scans in participants after one night of sleep deprivation. Aβ burden was increased in the right hippocampus and thalamus. I had a few observations and concerns about this paper:

    1. I would not have expected that amyloid PET would detect a change in Aβ burden after one night of sleep deprivation. A potential implication of this is that the rate of amyloid deposition per night of sleep deprivation could be determined. Then, the number of sleepless nights needed to become amyloid-positive could be calculated. An important follow-up question would be: Does the predicted number of sleepless nights make sense in the context of known sleep patterns in different populations?
    2. Aβ deposition was found to be increased in the right hippocampus and thalamus. These are not regions that develop Aβ plaques early in AD.
    3. In studies using Aβ stable isotope labeling kinetics (SILK), we see changes in Aβ42 kinetics with amyloid deposition. I would predict that sleep-deprived individuals would have altered Aβ42 kinetics if active overnight deposition was going on and we don’t see this.
  3. This study further highlights the growing interest in the field on how sleep is related to the regulation of Aβ levels in the brain. This is an important emerging area in the field that deserves greater exploration as sleep disturbances are well-documented in AD populations (Peter-Derex et al., 2014). The authors' findings that sleep deprivation increases levels of Aβ deposition in the brain is generally consistent with prior work examining sleep. However, there are a few caveats that should be considered when interpreting the study’s findings:

    1. Work with both animal (Kang et al., 2009) and human (Huang et al., 2012) models has shown that levels of Aβ in the ISF and CSF, respectively, have a diurnal rhythm. The mechanism of this relationship is thought to be due to the fact that Aβ levels are known to be regulated by neuronal activity (Cirrito et al., 2005). Subsequent studies have shown, in humans, that Aβ CSF levels are tied to sleep quality (Ju et al., 2013), slow-wave sleep (Ju et al., 2017), as well as sleep deprivation (Ooms et al., 2014). The majority of the literature reports relationships between sleep and soluble forms of Aβ.

    2. Florbetaben and other PET tracers bind to Aβ plaques (Fodero-Tavoletti et al., 2012), rather than the soluble forms of Aβ previously measured in animal and human work. While increased soluble forms of Aβ likely impact plaque formation, it is unclear if this process could occur over one day. Future work should focus on establishing the biological mechanism that could potentially lead to increased plaque deposition in the brain in such a short, one day, time frame. It would also be highly interesting to measure both CSF and PET measures to establish whether subject specific increase in fluid levels of Aβ are proportional to changes seen with PET.

    3. Given the young age of the participants (mean age 43, 40 percent of the population under 40) the majority of participants would be free of any plaque pathology. This means that any PET measurements are entirely dominated by non-specific binding. Additionally the observed results are also not in areas where Aβ deposition is typically seen using PET. This raises concerns that the experimental manipulation is affecting non-specific binding, tracer kinetics, or BBB permeability rather than facilitating plaque buildup.


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News Citations

  1. While You Were Sleeping—Synapses Forged, Amyloid Purged
  2. Skimping on Sleep Makes For More Aβ in the Brain
  3. Sleep Deprivation Taxes Neurons, Racks Up Brain Aβ?
  4. Does Daytime Drowsiness Foreshadow Aβ Accumulation?

Paper Citations

  1. . Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain. 2017 Aug 1;140(8):2104-2111. PubMed.
  2. . Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology. 2017 Aug 1;89(5):445-453. Epub 2017 Jul 5 PubMed.
  3. . Validation of Non-Invasive Tracer Kinetic Analysis of 18 F-Florbetaben PET Using a Dual Time-Window Acquisition Protocol. J Nucl Med. 2017 Nov 24; PubMed.
  4. . Amyloid tracers detect multiple binding sites in Alzheimer's disease brain tissue. Brain. 2013 Jul;136(Pt 7):2217-27. PubMed.
  5. . Pittsburgh Compound-B (PiB) binds amyloid β-protein protofibrils. J Neurochem. 2017 Jan;140(2):210-215. Epub 2016 Dec 12 PubMed.
  6. . Sleep deprivation and cerebrospinal fluid biomarkers for Alzheimer's disease. Sleep. 2018 May 1;41(5) PubMed.

Further Reading


  1. . The Relationship between Sleep Quality and Brain Amyloid Burden. Sleep. 2016 May 1;39(5):1063-8. PubMed.

Primary Papers

  1. . β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):4483-4488. Epub 2018 Apr 9 PubMed.