Knowing Neurons
SleepAgingCognitionNeurological and Psychiatric Disorders

Alzheimer’s Disease: When Brains Stay Up Past Bedtime

By Mary Bullock Cooper

Do you have a bedtime? If you answered no… I’m sorry, but everyone has a bedtime! This bedtime is unlike the one in childhood that is enforced by a parent and is instead enforced by your very own brain! To do this, your brain receives input from your retina about the light cycles outside to let your brain know what time of day it is. This allows your brain to tell time to your body in order to synchronize many important functions like sleeping, eating, and other behaviors (National Institute of General Medicine, 2022).

When light levels dim in the evening hours, melatonin synthesis and release begins. When this happens, our brain signals to the rest of the body that it’s time for bed. Sleep-promoting centers in the brain begin the carefully orchestrated release of hormones and chemicals that make us fall and stay asleep (Brzezinski, 1997). This daily rhythm in behavior is due to the body’s ability to maintain circadian rhythms, which are generated from a molecular clock inside of each cell in your body. Essentially, a group of genes, called clock genes, form a negative feedback loop with each other. In other words, these genes are able to turn their own expression off when their expression levels get too high. (Hastings et al., 1998). The cyclical nature of these clock gene expressions results in the cyclical functions in our body, such as melatonin release at night and eating patterns.

Sleep-promoting centers in the brain begin the carefully orchestrated release of hormones and chemicals that make us fall and stay asleep

Clock genes control critical aspects of the functions of every organ and tissue in the body (Rijo-Ferreira & Takahashi, 2019). But what happens when this molecular clock breaks? In Alzheimer’s Disease (AD) this is an important question, because among symptoms of memory loss are many additional disruptions in circadian rhythms and sleep such as timing & duration, behavior changes around sunset, and hyperactive neurons within the brain itself (Canevelli et al., 2016). In other words, brains with AD stay up past their bedtime, which could be a result of: 1) sundowning syndromes, 2) sleep fragmentation, and 3) epileptiform activity.

If you have known someone with AD, which is becoming more and more likely with our aging population (Alzheimer’s Association, 2023), then you may have experienced an event known as “sundowning”. This phrase comes from the term “Sundowning Syndrome” that is used to describe the various changes in mood & behavior that occur roughly around sundown each day in AD and other dementias. The exact cause of these symptoms is unknown but is thought to be a result of degeneration of sleep centers in the brain as the disease progresses. Sundowning frequently includes difficulty sleeping, anxiety, agitation, hallucinations, pacing and disorientation (National Institutes of Aging, 2017a). An additional challenge that sundowning poses is the burden it places on caregivers, who are likely at the end of a long day of work to need to rest themselves. This creates a severe decrease in the quality of life for the caretaker and person with the disease (National Institutes of Aging, 2017b). Current advice encourages low stimulation (low noise levels, limitting stress, etc.) at evening hours, regular rest to prevent exhaustion, and discussions with medical professionals to time things like meals and medications (Alzheimer’s Association, 2023).

“Sundowning Syndrome”… is used to describe the various changes in mood & behavior that occur roughly around sundown each day in AD and other dementias

Sleep fragmentation is yet another way that brains stay up past their bedtimes in the context of Alzheimer’s disease. Sleep fragmentation is the shortening of sleep duration and the increasing of wakefulness during the sleep cycle. This is commonly measured using actigraphy, which monitors a person’s sleep through a wearable device like a fitness watch. Studies using this method have found that older adults with sleep fragmentation had a higher risk of developing AD (Lim et al., 2013). Additional studies in mice see that sleep fragmentation is associated with degeneration in the brain as well as inflammatory responses that can promote neurodegeneration (Kaneshwaran et al., 2019). Additionally, extended wakefulness through sleep fragmentation causes a buildup of a pathogenic Alzheimer’s-related protein, amyloid-beta. The buildup of amyloid-beta, in turn, causes increased wakefulness, creating a destructive cycle (Vanderheyden et al., 2018). Taken together, these studies show that increased wakefulness during the times we should be asleep can promote damage in our brains that accelerates the neurodegenerative processes in AD.

Lastly, around 50% of patients with AD have subclinical epileptiform activity (non-convulsive seizures) during the night, particularly during sleep (Horvath et al., 2021). These seizures are detected by measuring the electrical activity in the brain via electrodes, such as in electroencephalography (EEG). During this epileptiform activity, neurons in the brain spike in bursts of hyper-synchronous activity (Jiruska et al., 2013). Typically, neurons are less prone to bursts of excitation at night due to the circadian molecular clock (Bothwell & Gillette, 2018), but the ability for our brains to tell time seems to be severely impaired in Alzheimer’s, resulting in a loss of cellular timekeeping and thus a loss of the ability to balance excitation and inhibition of neurons (Homolak et al., 2018). The cause of the seizure-like activity in AD is unknown, but it is associated with faster cognitive decline in people with AD, making it a serious issue that researchers are trying to solve (Horvath et al., 2021).

the ability for our brains to tell time seems to be severely impaired in Alzheimer’s, resulting in a loss of cellular timekeeping and thus a loss of the ability to balance excitation and inhibition of neurons

By now you have read about all of the problems that occur if our brains aren’t able to go to bed and stay in bed on time, but what are researchers doing about it? The field of circadian science is full of ideas for what could be causing things like sleep-fragmentation and sundowning, but time will tell if any of these ideas produce meaningful treatments for those with AD, and respite for their caretakers. Investigations into the clock genes that maintain the brain’s internal molecular clock are the main subject of investigation in many AD and circadian science labs. Researchers are hoping to discover what about the molecular clock makes brains with AD tick, and how we can reset their internal rhythms.

More attention is needed for circadian research and support of caretakers in managing circadian symptoms in people with AD. In fact, the National Institutes of Health are actively asking researchers to study circadian rhythms in AD for this very reason (American Academy of Sleep Medicine, 2018). While researchers work around the clock to come up with novel therapies, there are simple things you and your loved ones can do at home to maintain sleep hygiene and promote a healthy brain, the most important of these things being to get regular and plenty of sleep. So, tonight, when you start to feel your eyes get heavy, instead of fighting your internal call for bedtime, snuggle up to your favorite pillow and remember your brain has a bedtime for a reason.

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Written and Illustrated by Mary Bullock Cooper
Edited by Zoe Dobler, Keionna Newton, and Anastasiia Gryshyna

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a blue clock against a silhouette of a brain with a purple background

Further Reading

National Council on Aging: Aging and Sleep: Prevent Disease by Getting More Zzzs

 

References
Alzheimer’s Association. (2023). Alzheimer’s Disease Facts & Figures. https://www.alz.org/alzheimers-dementia/facts-figures#:~:text=The%20number%20of%20Americans%20living,are%20age%2075%20or%20older. Alzheimer’s Association. (2023). Sleep Issues & Sundowning. Retrieved from https://www.alz.org/help-support/caregiving/stages-behaviors/sleep-issues-sundowning

American Academy of Sleep Medicine. (2018, May 25). NIH recommends more research exploring sleep and circadian link to Alzheimer’s disease. Retrieved from https://aasm.org/nih-recommends-more-research-exploring-sleep-and-circadian-link-to-alzheimers-disease/.

Bothwell, M. Y., & Gillette, M. U. (2018). Circadian redox rhythms in the regulation of neuronal excitability. Free radical biology & medicine, 119, 45-55. https://doi.org/10.1016/j.freeradbiomed.2018.01.025

Brzezinski, A. (1997). Melatonin in Humans. New England Journal of Medicine, 336(3), 186-195. https://doi.org/10.1056/nejm199701163360306

Canevelli, M., Valletta, M., Trebbastoni, A., Sarli, G., D’Antonio, F., Tariciotti, L., de Lena, C., & Bruno, G. (2016). Sundowning in Dementia: Clinical Relevance, Pathophysiological Determinants, and Therapeutic Approaches. Frontiers in Medicine, 3, 73. https://doi.org/10.3389/fmed.2016.00073

Hastings, M. (1998). The brain, circadian rhythms, and clock genes. BMJ, 317(7174), 1704-1707. https://doi.org/10.1136/bmj.317.7174.1704

Homolak, J., Mudrovčić, M., Vukić, B., & Toljan, K. (2018). Circadian Rhythm and Alzheimer’s Disease. Medical Sciences, 6(3), 52. https://doi.org/10.3390/medsci6030052

Horvath, A. A., Papp, A., Zsuffa, J., Szucs, A., Luckl, J., Radai, F., Nagy, F., Hidasi, Z., Csukly, G., Barcs, G., & Kamondi, A. (2021). Subclinical epileptiform activity accelerates the progression of Alzheimer’s disease: A long-term EEG study. Clinical Neurophysiology, 132(8), 1982-1989. https://doi.org/10.1016/j.clinph.2021.03.050

Jiruska, P., de Curtis, M., Jefferys, J. G., Schevon, C. A., Schiff, S. J., & Schindler, K. (2013). Synchronization and desynchronization in epilepsy: controversies and hypotheses. The Journal of Physiology, 591(4), 787-797. https://doi.org/10.1113/jphysiol.2012.239590

Kaneshwaran, K., Olah, M., Tasaki, S., Yu, L., Bradshaw, E. M., Schneider, J. A., Buchman, A. S., Bennett, D. A., De Jager, P. L., & Lim, A. S. (2019). Sleep fragmentation, microglial aging, and cognitive impairment in adults with and without Alzheimer’s dementia. Science Advances, 5(12), eaax7331. https://doi.org/10.1126/sciadv.aax7331

National Center for Complementary and Integrative Health. (2023, May 9). Melatonin: What you need to know. Retrieved from https://www.nccih.nih.gov/health/melatonin-what-you-need-to-know.

National Institute on Aging. (2017, May 17). Tips for Coping with Sundowning Syndrome. Retrieved from https://www.nia.nih.gov/health/tips-coping-sundowning.

National Institute of Aging. (2017, May 1). What is Respite Care. Retrieved from https://www.nia.nih.gov/health/what-respite-care.

National Institute of General Medicine. (2022, May 4). Circadian Rhythms. Retrieved from
https://nigms.nih.gov/education/fact-sheets/Pages/circadian-rhythms.aspx

Lim AS, Kowgier M, Yu L, Buchman AS, Bennett DA. Sleep Fragmentation and the Risk of Incident Alzheimer’s Disease and Cognitive Decline in Older Persons. Sleep. 2013 Jul 1;36(7):1027-1032. doi: 10.5665/sleep.2802. PMID: 23814339; PMCID: PMC3669060.

Rijo-Ferreira, F., Takahashi, J.S. Genomics of circadian rhythms in health and disease. Genome Med 11, 82 (2019). https://doi.org/10.1186/s13073-019-0704-0

Vanderheyden, W.M., Lim, M.M., Musiek, E.S., Gerstner, J.R., 2018. Alzheimer’s Disease and Sleep–Wake Disturbances: Amyloid, Astrocytes, and Animal Models. The Journal of Neuroscience 38, 2901–2910. https://doi.org/10.1523/jneurosci.1135-17.2017

Author

  • Mary Cooper

    Mary Cooper is a Graduate Student in the Departments of Neurology and Psychology at the University of Alabama at Birmingham (UAB). She uses a range of techniques including mRNA hybridization, EEG, and behavioral machine learning programs to study circadian influences on Alzheimer’s Disease. Mary’s scientific pursuits outside the lab are to make useful connections between classical arts and academic sciences. She is a contributor and volunteer at the Brain Awareness Week celebrations in Birmingham, Alabama. In her spare time, Mary is a pianist, gardener, and painter.

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Mary Cooper

Mary Cooper is a Graduate Student in the Departments of Neurology and Psychology at the University of Alabama at Birmingham (UAB). She uses a range of techniques including mRNA hybridization, EEG, and behavioral machine learning programs to study circadian influences on Alzheimer’s Disease. Mary’s scientific pursuits outside the lab are to make useful connections between classical arts and academic sciences. She is a contributor and volunteer at the Brain Awareness Week celebrations in Birmingham, Alabama. In her spare time, Mary is a pianist, gardener, and painter.