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Sleep Loss Encourages Spread of Toxic Alzheimer’s Protein

Posted on by Dr. Francis Collins

Man sleeping
Credit: iStock/bowdenimages

In addition to memory loss and confusion, many people with Alzheimer’s disease have trouble sleeping. Now an NIH-funded team of researchers has evidence that the reverse is also true: a chronic lack of sleep may worsen the disease and its associated memory loss.

The new findings center on a protein called tau, which accumulates in abnormal tangles in the brains of people with Alzheimer’s disease. In the healthy brain, active neurons naturally release some tau during waking hours, but it normally gets cleared away during sleep. Essentially, your brain has a system for taking the garbage out while you’re off in dreamland.

The latest findings in studies of mice and people further suggest that sleep deprivation upsets this balance, allowing more tau to be released, accumulate, and spread in toxic tangles within brain areas important for memory. While more study is needed, the findings suggest that regular and substantial sleep may play an unexpectedly important role in helping to delay or slow down Alzheimer’s disease.

It’s long been recognized that Alzheimer’s disease is associated with the gradual accumulation of beta-amyloid peptides and tau proteins, which form plaques and tangles that are considered hallmarks of the disease. It has only more recently become clear that, while beta-amyloid is an early sign of the disease, tau deposits track more closely with disease progression and a person’s cognitive decline.

Such findings have raised hopes among researchers including David Holtzman, Washington University School of Medicine, St. Louis, that tau-targeting treatments might slow this devastating disease. Though much of the hope has focused on developing the right drugs, some has also focused on sleep and its nightly ability to reset the brain’s metabolic harmony.

In the new study published in Science, Holtzman’s team set out to explore whether tau levels in the brain naturally are tied to the sleep-wake cycle [1]. Earlier studies had shown that tau is released in small amounts by active neurons. But when neurons are chronically activated, more tau gets released. So, do tau levels rise when we’re awake and fall during slumber?

The Holtzman team found that they do. The researchers measured tau levels in brain fluid collected from mice during their normal waking and sleeping hours. (Since mice are nocturnal, they sleep primarily during the day.) The researchers found that tau levels in brain fluid nearly double when the animals are awake. They also found that sleep deprivation caused tau levels in brain fluid to double yet again.

These findings were especially interesting because Holtzman’s team had already made a related finding in people. The team found that healthy adults forced to pull an all-nighter had a 30 percent increase on average in levels of unhealthy beta-amyloid in their cerebrospinal fluid (CSF).

The researchers went back and reanalyzed those same human samples for tau. Sure enough, the tau levels were elevated on average by about 50 percent.

Once tau begins to accumulate in brain tissue, the protein can spread from one brain area to the next along neural connections. So, Holtzman’s team wondered whether a lack of sleep over longer periods also might encourage tau to spread.

To find out, mice engineered to produce human tau fibrils in their brains were made to stay up longer than usual and get less quality sleep over several weeks. Those studies showed that, while less sleep didn’t change the original deposition of tau in the brain, it did lead to a significant increase in tau’s spread. Intriguingly, tau tangles in the animals appeared in the same brain areas affected in people with Alzheimer’s disease.

Another report by Holtzman’s team appearing early last month in Science Translational Medicine found yet another link between tau and poor sleep. That study showed that older people who had more tau tangles in their brains by PET scanning had less slow-wave, deep sleep [2].

Together, these new findings suggest that Alzheimer’s disease and sleep loss are even more intimately intertwined than had been realized. The findings suggest that good sleep habits and/or treatments designed to encourage plenty of high quality Zzzz’s might play an important role in slowing Alzheimer’s disease. On the other hand, poor sleep also might worsen the condition and serve as an early warning sign of Alzheimer’s.

For now, the findings come as an important reminder that all of us should do our best to get a good night’s rest on a regular basis. Sleep deprivation really isn’t a good way to deal with overly busy lives (I’m talking to myself here). It isn’t yet clear if better sleep habits will prevent or delay Alzheimer’s disease, but it surely can’t hurt.


[1] The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, Finn MB, Manis M, Geerling JC, Fuller PM, Lucey BP, Holtzman DM. Science. 2019 Jan 24.

[2] Reduced non-rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease. Lucey BP, McCullough A, Landsness EC, Toedebusch CD, McLeland JS, Zaza AM, Fagan AM, McCue L, Xiong C, Morris JC, Benzinger TLS, Holtzman DM. Sci Transl Med. 2019 Jan 9;11(474).


Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)

Accelerating Medicines Partnership: Alzheimer’s Disease (NIH)

Holtzman Lab (Washington University School of Medicine, St. Louis)

NIH Support: National Institute on Aging; National Institute of Neurological Disorders and Stroke; National Center for Advancing Translational Sciences; National Cancer Institute; National Institute of Biomedical Imaging and Bioengineering


  • Dave Dayanan says:

    Thanks for the Article Doc, May I Ask are there any substitute vitamins that can help I always slept late at night.

    • Gary S Boenzi says:

      I’m not an expert, but i use Melatonin and Magnesium supplements that seem to help get to sleep and stay asleep. Exercise earlier in the day also is helpful. Reduce use of TV and electronic devices. The blue light from devices makes your brain want to wake up.

      • Mikaela says:

        Just a precision here: Melatonin will not necessarily make you fall asleep right away, but it helps regulate your sleep cycle. So mix taking Melatonin and having a regular sleep schedule, and you have a winning combination in the long run.
        I can’t say about Magnesium, since I don’t take it. The other two tips are highly recommended.

  • Rick Bogle says:

    The use of sleep deprivation in research using non-human animals is cruel. The use of sleep deprivation should be banned in all cases where informed consent is not given.

  • Diane Hart says:

    As a Health Educator, I will use this valuable information in my sleep seminars. Thank You.

  • Mark Headley says:

    Much compelling research reported “suggest[ing] that Alzheimer’s disease and sleep loss are even more intimately intertwined than had been realized. Yet the caveat “might” seems warranted: The association with tau and beta-amyloid accumulation might still indicate these markers, not culprits. Whether or not sleep deprivation, too, is a marker or culprit.

  • Jim Frame says:

    How can I sign up for these articles?

  • sbpm says:

    Always slept at night is one of my big problems in my health.
    May be this is one of why my body is getting bigger and bigger.
    Can I have any advice..?

  • Sylvia F Jutila says:

    So how can I sleep better? Melatonin doesn’t do anything. I get 2 1/2 hours from Sonata but I don’t dare take them more than 2 or 3 times a week because I am afraid they will quit working. I do the relaxation routine, go to bed at 10 and get up at 7 and lay awake for 2 or 3 hours a night, sometimes more. I don’t watch TV at night, I turn all the lights off, our house is very quiet. i don’t have a clue as to what else I can do.

  • Rebecca G says:

    My question is similar: Melatonin doesn’t do anything for me. Ambien works, but I don’t want to become dependent. I lead a very low-stress life, and allot plenty of time for sleep, but my body just seems to have forgotten how. Given the choice between medicating to sleep, or not sleeping enouggh, which is the better option? And are there medications which are safe to take regularly and long-term? I’ve read about THEIR effects on brain health as well.

    • Ann D. says:

      I have the same problems and it doesn’t help to lie awake wondering if you are causing Alzeheimer’s or maybe a heart attack, which is also blamed on lack of sleep. Hope someone who knows will answer Rebecca’s (and my) questions.

  • Stephen B. says:

    After finding that I had sleep apnea and treating it with use of a CPAP machine I find my thinking clearer and my visual thinking skills back to the level that they were thirty years ago.

  • Kelly Burgess says:

    Is there a similar link btw sleep deprivation or the lack of REM sleep and incidences of of other degenerative diseases e.g. PSP?

  • Brittany says:

    Great read! My mom has dementia and it continues to worsen every month. I do a lot of reading of ways to help her feel better or slow it down. I read that hearing aids can reduce the risk of dementia. What are your thoughts?

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