by Lina Hamid and Christopher M. Cirino, DO MPH

Introduction

This article highlights two key issues: sleep and dementia. Ever-growing support in the literature associates impaired sleep with an increased likelihood of dementia. We will see rises in dementia associated with the aging cohort, so that, by 2060, there could be 14 million people in the US living with dementia. 

Sleep is a body function critical for survival. We know this because total sleep deprivation studies in rats ended in death within 11 to 32 days. A recent article (2020) implicated the gut as playing a role in death by reactive oxygen species (ROS) from a stress reaction. Clearly, sleep has a multi-system effect on the body.

Sleep disorders are increasingly more common in this technology-heavy age. An estimated 70 million people in the US experiencing trouble falling or staying asleep. Sleep problems frequently overlap with cognitive dysfunction and other neurologic diseases. There is growing evidence that implicates sleep deprivation as an independent risk factor for dementia and requires increased attention.

Dementia on the Rise

Dementia Prevalence

An estimated 5.8 million Americans over the age of 65 are living with dementia. Health experts predict that this amount will double within the next few decades. Dementia is a major cause of death, with an increase over the last few decades to become the leading cause of death in the UK. During the COVID-19 pandemic, there was an increase in dementia-related deaths. Among the main reasons was that patients with Alzheimer’s dementia and COVID-19 had a higher risk for death.

The US health care system spends an estimated $250 to $305 billion yearly for the treatment costs, caregivers, and support systems for those living with dementia-and this expense is expected to increase.

Disease and Associated Conditions

Dementia is a neurodegenerative disorder. This condition impairs multiple areas of the brain, making daily living difficult for people who have this cognitive disorder. Dementia creates a dependency on others for support and robs individuals of their physical and mental mobility. Along with an individual’s challenges and the impact it has on the family are significant disease comorbidities associated with dementia, including diabetes mellitus, peripheral vascular disease, and cerebrovascular disease.

Types of Dementia

There are several types of dementia disorders, the most common is Alzheimer’s dementia (AD); vascular dementia ranks as the second most cause. The areas of the brain associated with learning and memory become damaged by beta-amyloid plaques and neurofibrillary tangles (NFT). The major protein found in excess in the brains of those with AD is referred to as the tau protein (Avila). For additional information on AD, check this YHF link. 

There is still some question as to how plaques and tangles occur and damage brain cells. The defects in the brain could be a result of amyloid protein changing shape and damaging the nerve synapses-a process that occurs before plaques even become detectable. Impaired amyloid pools can cause nearby healthy amyloids to go into disruption mode and start to mutate. Subsequently, the amyloid and tau, another protein, forms onto plaques and tangles. We’ll occasionally refer to these proteins as “toxins” in this article.

The Link of Sleep into the Dementia

Sleep and dementia are bidirectional issues, meaning that sleep deprivation contributes to dementia and dementia contributes to sleep deprivation. This may occur because of sleep’s main objective for the brain: the clearance of toxins in the brain, the same toxins that cause AD. In dementia, sleep is disturbed because of toxin build-up.

In a recently published cohort study (2021) by Sabia and colleagues, persistent short sleep durations in midlife were associated with a 30 percent increase in the risk of late-onset dementia. The study included 8000 participants recruited in 1985 and followed for thirty years. It interestingly revealed a U-shaped distribution between sleep duration and dementia, with the “sleep (sweet) spot” around 7-9 hours of duration, where less sleep or more sleep was associated with increased dementia.

The Neurovascular Unit and Neurovascular Coupling: A deeper look

The brain must receive uninterrupted blood flow. The system of neural structures and cerebral blood vessels is referred to as a neurovascular unit (NVU). Neurons do not have direct contact with blood. Instead, flow is compartmentalized. Astroglia, or astrocytes, form the center of a three-part system and are directly associated with both microvessels and adjacent neurons. They regulate the number of metabolites, such as glucose, lactate, and ketone bodies, to and from neurons,

The status of neurons in the brain is contingent upon astroglia in the NVU. The brain regulates blood flow, prevents leaks, and protects against harmful toxin buildup (including infectious agents). An equilibration process known as neurovascular coupling ensures that blood flow is matched correctly to neuron activity. Any disruption to neurovascular coupling can cause neurological disorders or blood disturbances. Damage to the astroglia is likely triggered by a process similar to other cells – oxidative stress, the likely contributor to many neurologic disorders.

Key point: Conditions such as atherosclerosis ( the thickening of blood vessels), hypertension, and AD impair blood vessels and blood flow and supply to the brain, leading to vascular dysfunction and a breakdown in neurovascular coupling. As a result, metabolites, toxins, and cerebrovascular radicals build up in these conditions.

The Benefits of Sleep

Sleep Deprivation Changes the Brain

Sleep loss likely accelerates dementia and affects short-term memory, learning ability, and decreased motor performance and motor skills. It can bring about unwanted changes in the hippocampus region of the brain. There can be alterations in brain chemicals and signaling molecules where there is sleep deprivation. Changes in the vascular walls that interfere with blood flow are problematic for vascular elasticity and vascular arterial compliance.

Sleep deprivation leads to the build-up of beta-amyloid and affects the brain’s glymphatic system. These topics are addressed in this section.

Beta-amyloid

Beta-amyloid is a toxic protein found in sleep-deprived patients. It collects to create plaque. Beta-amyloid is toxic and collects in the fluid between brain cells. This plaque disturbs communication between neurons, likely a result of the destruction of neural synapses.

Changes take place in the thalamus and hippocampus. These two brain regions play their part in mood management. Large quantities of beta-amyloid can make patients moody. Sleeping washes away beta-amyloid. 

In a study by the National Institute of Alcohol Abuse and Alcoholism, participants between the ages of 22 and 72 were used to investigate what happens to the brain after 31 hours of sleep deprivation. A tracer was used to measure beta-amyloid. The results showed that beta-amyloid went up by about 5% after 31 hours of sleep deprivation. The study showed brain changes in the thalamus and hippocampus. 

The amount of beta-amyloid deposits in participants was associated with a worse mood after sleep deprivation. This study and others have found that both the thalamus and hippocampus of the brain play a role in mood and emotion and that sleep plays an integral part in mood regulation.

The Brain’s Glymphate System

The brain does not possess a true lymphatic system. It uses a system that has some similarities, known as the glymphatic system. The brain pulsates the cerebrospinal fluid with the vascular system. Sleep clears the brain’s glymphatic system of amyloid-Beta peptides, a peptide that plays an important role in the development of amyloid plaques found in Alzheimer’s.

The brain contains a fluid (the cerebrospinal fluid, or CSF) that washes away toxins and other debris out of the central nervous system. This action through the modulation process helps to clear harmful substances from the brain.

Summary

Examples of the overlap of sleep and cognitive function are numerous. Dementia and sleep are interrelated, where sleep deficit can lead to memory impairment and a build-up of changes in the brain that have been causally linked to dementia; dementia can lead to sleep impairment which worsens dementia.

Sleep conserves energy, recycles energy, repairs cell tissue, allows for thermoregulatory and metabolic regulation, and maintains the adaptive immune system. Sleep detoxifies the brain, removing accumulated waste via the glymphatic system, and plays an essential role in preserving memory. Prioritizing sleep hygiene may be the best defense against the risk of dementia. 

Sleep is a Gordian knot, both contributing to dementia and worsened by dementia. Sleep is a crucial function for the body. It is likely that unraveling ways to preserve health, and delay dementia, and optimal sleep will result in the same endpoint: longevity and the persistence of the optimal functioning of the human body.

References 

Alzheimer’s Organization, Plaques, and Tangles. https://www.alzheimersorganization.org/plaques-and-tangles-d 

Avila J. Tau protein, the main component of paired helical filaments. J Alzheimers Dis. 2006; 9(3 Suppl): 171-5. doi 10.3233/jad-2006-9s320. Accessed 8/6/2021.

Brown GM, Light, Melatonin and the Sleep-Wake Cycle. J Psychiatry Neurosci. (Nov 1994) https://pubmed.ncbi.nlm.nih.gov/7803368/ 

Everson C, Bergmann B, Rechtschaffen A. Sleep derivation in the rate; III. Total sleep deprivation. Sleep. 1989 Feb; 12(1):13-21. doi: 10.1093/sleep/12.1.13. Accessed abstract on 8/5/2021.

Girouard H, Idecola C. Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer’s disease. 2005. J Appl Physiol. 100(1):328-35. doi: 10.1152/japplphysiol.00966.2005. Accessed 8/6/2021.

Gorelick P and Scuteri A, Vascular Contributions to Cognitive Impairment and Dementia ( 2011 July 21). Stroke, 42 (9), 2672-2713 Doi: 10.1161/STR.0b013e3182299496 (2000, 600 million figures from here

Kaczynski A, et al. Comorbidity in Dementia Diseases and Associated Health Care Resources Utilization and Cost. Journ Alz Dis. 68(2): 635-646. DOI: 10.3233/JAD-180896. Abstract accessed 8/5/2021.

Kramarow E and Vera Betzaida, Dementia Mortality in the United States. (March 14, 2019) link National Vital Statistics Reports Volume 68, Number 2 March 14, 2019 (cdc.gov)

Lammers M and Ahmed A, Melatonin for Sundown Syndrome and delirium in Dementia: Is it Effective? (June 14, 2013) https://doi.org/10.1111/jgs.12296 

Li, K., Luo.,Zeng Q, Interactions between sleep disturbances and Alzheimer’s disease on brain function: a preliminary study combining the static and dynamic functional MRI. Sci Rep 9, 19064 (2019). DOI: 10.1038/s41598-019-55452-9 

Maiese K, Impacting dementia and cognitive loss with innovative strategies: mechanistic target of rapamycin, clock genes, circular non-coding ribonucleic acids, and Rho/Rock. (May 2019) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375029/

Mahalakshmi A.M, Ray B and Tuladhar S. (2020) . Sleep, brain vascular health, and aging. GeroScience,42(5), 1257 -1283. DOI: 10.1007/s11357-020-00235-8

McCleery J and Cohen D, Pharmacotherapies for sleep disturbances in dementia. (November 2016) https://.www.ncbi.nlm.nih.gov.pmc/articles/PMC6464889/

National Institutes of Health, Sleep deprivation increases Alzheimers protein. (2018, April 24). https://www.nih.gov/news-events-research-matters-/sleep-deprivation-increases-alzheimers-protein

NHS, Vascular Dementia. https://www.nhs.uk/conditions/vascular-dementia/  

Rasch B and Born J, About Sleep’s Role in Memory. (2019, April 01). Doi:10.1152/physrev.00032.2012 

Rose, K, Fagin C, and Lorenz R, Sleep disturbances in dementia: What they are and what to do. ( 2010 May 06). J Gerontol Nurs,36(5), 9-14 Doi: 103928/00989134-20100330-05

Sabia, S., Fayosse, A., Dumurgier, J Association of sleep duration in middle and old age with incidence of dementia. Nat Commun 12, 2289 (2021). Doi: 10.1038/s41467-021-22354-2

Shenker J and Singh G, Sleep and Dementia. (2017, Jul-Aug) https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6140093/   ( statistics about 70 million people and study percentages)

Stanford S C, Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. (July 24, 2018) https://www.ncbi.nlm.gov/pmc/articles/PMC6057894/ 

Takahashi S. Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit. Neuropathology 2020; 40, 121-137.

Vaccaro A, et. al. Sleep Loss Can Cause Death through Accumulation of Reactive Oxygen Species in the Gut. Cell. 2020. Jun 4. 181(6): 1307-1328. E15.

Wolters F and Ikram Arfan, Epidemiology of Vascular Dementia. (July 11, 2019) https://doi.org/10.1161/ATVBAHA.119.311908