Could prioritizing deep sleep be the key to protecting your brain? Scientists uncover how sleep disturbances may accelerate neurodegeneration—and why improving sleep could help delay cognitive decline.

Review: The night’s watch: Exploring how sleep protects against neurodegeneration. Image Credit: metamorworks / Shutterstock

Can better sleep help prevent or delay neurodegenerative diseases? Millions suffer from dementia worldwide, yet the relationship between sleep disturbances and cognitive decline remains complex.

In a recent review published in the journal Neuron, Washington University scientists explored whether disrupted sleep contributes to neurodegeneration, serves as an early symptom, or both. By understanding sleep’s protective mechanisms, they aimed to uncover ways to enhance brain health and resilience.

Sleep and brain health

Researchers found that sleep disturbances may disrupt the brain’s ability to clear toxic proteins, potentially speeding up neurodegeneration.

Sleep restores brain function, consolidates memory, and removes toxic waste. However, as people age, sleep duration shortens, sleep becomes more fragmented, and deep sleep decreases—changes linked to cognitive decline and increased risk of neurodegenerative diseases.

Disruptions in non-rapid eye movement (NREM) sleep, particularly slow-wave sleep (SWS), are associated with early amyloid-beta (Aβ) plaque buildup and tau protein tangles, hallmarks of Alzheimer’s disease. Other neurodegenerative diseases, including Parkinson’s, Lewy body dementia, and frontotemporal dementia, often present with sleep disturbances years before cognitive symptoms appear.

Despite these associations, whether sleep disruptions drive neurodegeneration, reflect early pathology, or both remain uncertain. Understanding sleep’s role in brain health could lead to early interventions to delay or mitigate neurodegenerative diseases.

The current study

The study highlights how prolonged wakefulness increases neuronal activity, which can trigger inflammation and oxidative stress—both linked to cognitive decline.

The researchers examined how sleep disruptions might contribute to cognitive decline, analyzing sleep patterns, brain activity, and molecular markers in both human and animal models.

They explored sleep architecture—especially changes in NREM and REM sleep—and their impact on neurodegenerative pathways. They also investigated sleep’s role in clearing metabolic waste, such as amyloid-beta and tau, but noted conflicting evidence on whether sleep consistently enhances clearance efficiency.

The study assessed how prolonged wakefulness and fragmented sleep affect neuronal activity, neuroinflammation, and brain homeostasis. Findings from animal models suggested that sleep deprivation accelerates neurodegeneration by increasing protein deposition and disrupting neuronal function.

Additionally, the study examined neurotransmitters like orexin, dopamine, and acetylcholine in regulating sleep-wake cycles and their influence on disease progression. Researchers also explored genetic predispositions to poor sleep, analyzing variants such as APOE4, DEC2, ABCA7, and TREM2 to determine their role in cognitive decline.

Key insights

Not all sleep disturbances are the same—Alzheimer’s, Parkinson’s, and frontotemporal dementia each affect sleep in different ways, suggesting a deeper connection between brain disease and sleep patterns.

The study found that disrupted sleep may contribute to neurodegeneration while also serving as an early symptom. Poor sleep was linked to increased accumulation of neurotoxic proteins, impaired clearance, and heightened neuronal activity, triggering inflammation and oxidative stress.

In both human and animal models, fragmented sleep and reduced slow-wave sleep correlated with early neurodegenerative changes. Those with genetic predispositions, such as APOE4 carriers, experienced more significant sleep disturbances and a higher dementia risk.

Different neurodegenerative disorders exhibited distinct sleep patterns. Alzheimer’s disease was associated with sleep fragmentation, while Parkinson’s and frontotemporal dementia often involved excessive daytime sleepiness and REM sleep behavior disorder.

Improving sleep—through behavioral changes, pharmacological interventions, or sleep therapies—mitigated neurodegenerative processes in experimental models. Enhancing slow-wave sleep reduced amyloid burden and improved cognitive function in animal studies.

However, researchers noted knowledge gaps, particularly in distinguishing causation from correlation in human studies. While sleep disturbances are linked to neurodegeneration, more research is needed to determine whether sleep interventions can delay disease onset.

Conclusions

The study reinforced the critical role of sleep in brain health, suggesting that sleep disturbances may accelerate neurodegeneration rather than just accompany it. Enhancing sleep quality, particularly deep sleep, could help protect against cognitive decline. Further research is needed to validate sleep-focused therapies in humans, but prioritizing sleep health may be essential in reducing neurodegenerative disease risk.

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A new study found that a gene recently recognized as a biomarker for Alzheimer’s disease is actually a cause of it, due to its previously unknown secondary function. Researchers at the University of California San Diego used artificial intelligence to help both unravel this mystery of Alzheimer’s disease and discover a potential treatment that obstructs the gene’s moonlighting role.

The research team published their results on April 23 in the journal Cell.

About one in nine people aged 65 and older has Alzheimer’s disease, the most common cause of dementia. While some particular genes, when mutated, can lead to Alzheimer’s, that connection only accounts for a small percentage of all Alzheimer’s patients. The vast majority of patients do not have a mutation in a known disease-causing gene; instead, they have “spontaneous” Alzheimer’s, and the causes for that are unclear.

Discovering those causes could ultimately improve medical care.

“Unfortunately, treatment options for Alzheimer’s disease are very limited. And treatment responses are not outstanding at this moment,” said study senior author Sheng Zhong, a professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.

So Zhong and his team took a closer look at phosphoglycerate dehydrogenase (PHGDH), which they had previously discovered as a potential blood biomarker for early detection of Alzheimer’s disease. In a follow-up study, they later found that expression levels of the PHGDH gene directly correlated with changes in the brain in Alzheimer’s disease; in other words, the higher the levels of protein and RNA produced by the PHGDH gene, the more advanced the disease. That correlation has since been verified in multiple cohorts from different medical centers, according to Zhong.

Intrigued by this reproducible correlation, the research team decided to investigate in this latest study whether there was a causal effect. Using mice and human brain organoids, the researchers found that altering the amounts of PHGDH expression had consequential effects on Alzheimer’s disease: lower levels corresponded to less disease progression, whereas increasing the levels led to more disease advancement. Thus, the researchers established that PHGDH is indeed a causal gene to spontaneous Alzheimer’s disease.

In further support of that finding, the researchers determined—with the help of AI—that PHGDH plays a previously undiscovered role: it triggers a pathway that disrupts how cells in the brain turn genes on and off. And such a disturbance can cause issues, like the development of Alzheimer’s disease.

Moonlighting role

PHGDH creates an enzyme key for the production of serine, an essential amino acid and a neurotransmitter. Because PHGDH’s enzymatic activity was its only known role, the researchers hypothesized that its metabolic function must be connected to an Alzheimer’s outcome. However, all their experiments designed to prove so failed.

New research reveals that toxic air can reshape gene activity in the brain, potentially setting the stage for Alzheimer’s and Parkinson’s, underscoring the need for early detection and stronger protections for at-risk workers.

Review: Impact of Air Pollution and Occupational Inhalation Exposures on Neurodegenerative Disorders: an Epigenetic Perspective. Image Credit: IngeBlessas / Shutterstock

In a recent review article published in the journal iScience, researchers in Italy explored how air pollution contributes to neurodegenerative disorders (NDs) through epigenetic modifications. They highlighted the potential of using epigenetic markers to detect early changes triggered by air pollution, especially in high-risk groups. They stressed the need for further research to guide occupational and preventive health strategies.

Background

Young adults in polluted cities show alarming brain changes. Reduced histone markers (H3K9me2/me3) and increased DNA damage signals were found in their brain tissue, mirroring Alzheimer’s pathology decades before the typical diagnosis age.

NDs are long-term diseases that involve the loss of nerve cells in the brain or nervous system, resulting in significant issues with memory, thinking, mood, and physical function. Alzheimer’s disease and Parkinson’s disease are the most common, affecting millions of people globally. As populations age, the number of people with these conditions is rising. Many cases are linked to preventable risk factors, including poor lifestyle habits, low education or income, and exposure to environmental pollution.

Air pollution consists of harmful particles and gases from natural sources, such as wildfires, and human activities, including fuel burning, traffic, and factory emissions. Particulate matter can carry toxic substances, including heavy metals, bacteria, and volatile chemicals. Though primarily associated with heart and lung diseases, air pollution is now also linked to brain damage and increased risk of NDs. Certain workers, such as miners, factory workers, and drivers, may be especially at risk.

How air pollution affects the brain

Air pollution can impact brain health through two primary pathways: direct and indirect. The direct pathway involves ultrafine particles and certain gases that can enter the bloodstream or travel through the nose to the brain, potentially damaging the blood-brain barrier (BBB) and causing inflammation. Some pollutants, such as nitrogen dioxide (NO₂), convert into active compounds that affect brain function, while others, like volatile organic compounds (VOCs), can accumulate in brain tissue due to their fat-soluble nature. Though evidence of direct brain effects from these pollutants remains limited, studies have shown that substances like nanoplastics, lead, and manganese can cross the BBB and harm brain cells.

The indirect pathway involves pollutants triggering inflammation or chemical signals (like cytokines, extracellular vesicles, or lung/brain-derived exosomes) in organs like the lungs or gut. These molecules then travel through the bloodstream to the brain, disrupting its balance and possibly leading to cognitive and emotional problems. Air pollution may also disturb gut and nasal microbes, affecting brain health through the gut-brain or olfactory-brain axes. While experimental evidence is still emerging, understanding these mechanisms may help identify early biomarkers of pollution-related brain damage, especially in at-risk populations like workers in polluted environments.

Epigenetic pathways

Brain cells release distress signals into blood. Extracellular vesicles carrying epigenetic material from damaged neurons and astrocytes could become detectable early-warning biomarkers, creating a “message in a bottle” from the brain.

Epigenetic changes regulate brain function without altering deoxyribonucleic acid (DNA) sequences. These changes are vital for brain development, synaptic plasticity, and memory, but are also sensitive to environmental exposures, such as air pollution. Chronic exposure to pollutants can disrupt these epigenetic processes, potentially leading to NDs. Evidence suggests that such exposure may increase the expression of harmful genes, reduce the activity of protective genes, and alter non-coding ribonucleic acids (RNAs). These changes can occur long before symptoms arise, highlighting epigenetics as both a risk factor and an early biomarker for NDs.

Airborne pollutants can disrupt brain function by altering non-coding RNAs and DNA methylation, both of which regulate gene expression. Animal and human studies show these changes are linked to memory loss, inflammation, and NDs. However, most human evidence comes from peripheral blood samples, not brain tissue, limiting clinical interpretation. Toxins such as toluene, manganese, and lead can reduce the activity of protective genes or increase the production of harmful proteins in the brain. Some effects may even be passed to offspring. Air pollution also alters DNA methylation in blood and brain tissue, potentially increasing disease risk across the lifespan, especially with early or long-term exposure.

Few studies have explored how air pollution affects histone modifications in neurodegenerative diseases (NDs), due to technical challenges. However, early findings show links between air pollution and altered histone markers, DNA damage, and Alzheimer’s disease pathology in both humans and mice. Prenatal exposure to particulate matter affects brain development, particularly in males, due to impaired histone demethylation, highlighting sex-specific vulnerabilities. Plastic particles and heavy metals also disrupt histone modifications, causing oxidative stress, memory loss, and neuroinflammation. Notably, some experimental evidence for histone modifications (e.g., manganese-induced changes) comes from injection-based studies rather than inhalation exposure, creating uncertainty about real-world inhalation risks. Histone deacetylase inhibitors and compounds like butyrate (studied in lead-exposed mice) show potential in reversing some of these effects, offering avenues for future ND treatments.

Conclusions

Workers handling plastics face invisible threats. Nanoparticles from manufacturing or damaged respiratory equipment enter the brain, causing temporary olfactory damage and triggering inflammation – early warning signs for neurodegenerative diseases.

Recent research shows strong links between air pollution and NDs mainly through epigenetic changes. Pollutants can alter DNA methylation, non-coding RNA expression, and histone modifications, all of which contribute to brain inflammation and damage. New methods like analyzing extracellular vesicles in blood may help detect these changes without invasive procedures. However, studying histone modifications remains technically challenging. Major gaps remain. Real-world air pollution is complex, making it hard to study precise effects. Factors like particle size, individual health, and early-life exposure influence risk but are not fully understood. Anatomical differences between animal models and humans (e.g., nasal structure) further complicate translation of inhalation studies. Most research focuses on older adults, short-term exposure, and a limited number of pollutants, overlooking long-term and early-life effects. Diseases like multiple sclerosis, amyotrophic lateral sclerosis (ALS), and Huntington’s disease are also under-researched.

Future studies should be long-term, include younger populations, and consider less-studied pollutants and exposure routes, such as diet or gut-brain interactions. Combining omics technologies and artificial intelligence could help identify biomarkers and lead to the development of preventive therapies. Improved workplace and environmental protections, especially for high-risk groups, are also essential to reduce ND risk. Addressing regulatory implications requires validating epigenetic tools for clinical use.

People who spend less time in deep sleep or rapid eye movement (REM) sleep may be at greater risk for brain changes linked to Alzheimer’s disease. A new study published in the Journal of Clinical Sleep Medicine found that lower proportions of slow wave and REM sleep were associated with smaller volumes in certain brain regions that tend to show early signs of atrophy in Alzheimer’s. These findings suggest that sleep quality may play an important role in brain aging and could be a modifiable risk factor for dementia.

Alzheimer’s disease is a progressive neurodegenerative condition that slowly erodes memory and thinking skills. It affects more than 6 million older adults in the United States. One of the main features of the disease is brain atrophy, or the gradual loss of brain volume, particularly in areas like the hippocampus and parietal lobe. These structural changes typically begin years before symptoms appear. Researchers have long been interested in understanding what contributes to this atrophy and whether any lifestyle factors might influence it.

Sleep has emerged as one of the potential contributors. Poor sleep is common among older adults, and evidence has shown that disruptions in sleep can increase the risk of cognitive decline and dementia. Most earlier studies have relied on self-reported sleep habits, which can be inaccurate. Others have focused more on general sleep duration rather than the specific stages of sleep. The current study aimed to fill this gap by using objective, clinical-grade sleep measurements and by focusing on specific sleep stages—slow wave sleep and REM sleep—which are thought to be particularly important for brain health.

“On a personal level, three of my grandparents had dementia, which led me to study the broader topic of Alzheimer’s disease. I investigated this specific topic because there is not a lot of evidence on sleep architecture and region-specific atrophy,” said lead author Gawon Cho, a postdoctoral associate at Yale School of Medicine.

The research team analyzed data from a long-running study called the Atherosclerosis Risk in Communities (ARIC) Study, which has been following the health of U.S. adults for several decades. Between 1996 and 1998, a subset of participants underwent overnight sleep monitoring in their homes using a technique called polysomnography. This method records brain waves, heart rate, breathing, and muscle activity to determine what stage of sleep a person is in throughout the night. Over a decade later, between 2011 and 2013, some of the participants underwent brain imaging as part of a follow-up study.

For this study, researchers focused on 270 individuals who had both sleep and brain imaging data available and who had no signs of stroke or dementia at the time of the sleep assessment. The team used high-resolution magnetic resonance imaging (MRI) scans to measure the volume of specific brain regions known to be vulnerable to Alzheimer’s disease. These included the inferior parietal lobe, cuneus, precuneus, hippocampus, and entorhinal cortex. They also looked for small areas of brain bleeding called cerebral microbleeds, which are linked to vascular damage and may signal an increased risk of cognitive impairment.

The researchers then looked at whether the amount of time people spent in each sleep stage was related to the size of these brain regions years later. They accounted for many other factors that could influence brain health, such as age, sex, education, medical conditions, alcohol use, smoking history, and genetic risk for Alzheimer’s.

The results showed a clear pattern: people who spent less time in slow wave sleep and REM sleep tended to have smaller volumes in certain brain areas. Specifically, lower amounts of slow wave sleep were linked to reduced size in the inferior parietal and cuneus regions. Less REM sleep was associated with smaller volumes in the inferior parietal and precuneus areas. These findings remained statistically significant even after adjusting for other health and lifestyle factors.

Among the regions analyzed, the inferior parietal lobe showed the strongest association with both reduced slow wave and REM sleep. This part of the brain plays a role in memory, spatial reasoning, and attention—and it tends to shrink early in the course of Alzheimer’s disease. The researchers did not find any significant links between sleep quality and the presence of cerebral microbleeds, suggesting that the effects of poor sleep on brain structure may be independent of small vessel disease.

“The results were in the direction I expected,” Cho told PsyPost. “It was interesting that I found an association in the inferior parietal region, which plays a role in the synthesis of sensory information, given that visuospatial deficits can be observed in early Alzheimer’s disease.”

One of the interesting aspects of this study is that it also examined whether the association between sleep and brain atrophy differed depending on whether someone carried the APOE4 gene, a well-known genetic risk factor for Alzheimer’s. Although prior studies in animals and humans have found that APOE4 carriers may be more sensitive to the effects of poor sleep, this study did not find significant differences based on APOE genotype. However, the authors noted that their sample consisted entirely of white participants, which may have influenced the results. Other research has shown that racial and ethnic background can affect how sleep and genetic risk factors interact.

The study also considered the possibility that smaller brain volumes might cause changes in sleep architecture, rather than the other way around. While this kind of reverse relationship is possible, the researchers argued that it is more likely that sleep patterns influence brain structure in this case. They point to other studies showing that sleep deprivation can reduce activity in the parietal lobe and that persistent poor sleep may contribute to longer-term structural decline in this area.

These findings support the idea that deep, restorative sleep may help protect the brain against aging and disease. Slow wave sleep and REM sleep are thought to play key roles in memory consolidation and brain repair. Both stages also help clear waste products from the brain, including amyloid-beta, a protein that builds up in Alzheimer’s disease. If sleep disruptions reduce the brain’s ability to carry out these cleaning and maintenance processes, that could contribute to the gradual shrinkage seen in key brain regions.

While the study has many strengths—including the use of objective sleep measurements, long follow-up period, and detailed brain imaging—it also has several limitations. The participants were all white and generally healthier than the broader population, which may limit how generalizable the findings are. The number of participants with microbleeds was relatively small, reducing the ability to detect subtle associations.

Importantly, because the study is observational, it cannot prove that poor sleep causes brain atrophy—only that there is a connection. “The study does not demonstrate causality,” Cho said.

Future studies will be needed to confirm these findings in larger and more diverse populations, and to test whether improving sleep can actually slow or prevent the brain changes associated with dementia. Cho said she is also “looking to examine mechanisms underlying the observed association, focusing on brain waste clearance.”

The study, “Lower slow wave sleep and rapid eye movement sleep are associated with brain atrophy of AD-vulnerable regions,” was authored by Gawon Cho, Adam P. Mecca, Orfeu M. Buxton, Xiao Liu, and Brienne Miner.

Researchers have outlined a pathway by which human herpesvirus may contribute to Alzheimer’s disease (AD) in the aging brain. In a report published in Alzheimer’s & Dementia, a Cleveland Clinic-led investigative team also identified two commercially available antiviral drugs that reverse this pathway in a laboratory setting.

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The findings are the first concrete evidence to support the previously controversial link between human herpesviruses (HHVs) and AD. Illustrating the potential for herpes to trigger dementia bolsters continued efforts to prevent and cure neurodegenerative disease, says the report’s senior author, Feixiong Cheng, PhD, Director of Cleveland Clinic’s Genome Center. “Our analysis provides associations linking molecular, clinical and neuropathological features of Alzheimer’s with human herpesvirus infection, which warrants future clinical validation,” he notes.

When immune suppression of HHVs is lost

Many HHVs are individually present in a large percentage of people worldwide, and virtually every human being is expected to contract at least three types of HHV by adulthood. Some HHV infections produce no symptoms, while others cause typically nonserious illnesses such as mononucleosis or chickenpox. However, even after these illnesses subside, an infected individual still carries HHV for the rest of his or her life.

While HHVs are generally harmless when they are suppressed, mounting evidence shows that the human immune system can lose the ability to suppress them. This can happen naturally with advancing age, during pregnancy or after an illness. Recent research has shown that as HHVs become more active, they may trigger conditions such as pregnancy complications, cancer, birth defects and developmental delays in children.

Mounting data suggest that human herpes simplex virus-1 (HSV-1) and other HHVs are underexamined risk factors for diseases of old age. Circumstantial evidence has linked HSV-1 to AD pathogenesis and progression, but mechanisms underlying the link have remained uncertain.

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Transposable elements link HSV-1 and Alzheimer’s

Dr. Cheng hypothesized that latent HSV-1 infection could trigger AD by directly activating the transposable elements that the Cheng laboratory had previously connected to disease progression in aging brains.

Transposable elements, known colloquially as “jumping genes” or “viral elements,” are pieces of DNA that pop out of the chromosome and insert themselves elsewhere in the genome. The elements reintegrate into these new genome regions, disrupting the function of the genes they interrupt. Almost half of the human genome is made up of transposable elements, and the elements become more active with advancing age.

After previously mapping all transposable elements that are associated with AD in the aging brain (Alzheimers Dement. 2024;20[11]:7495-7517), Dr. Cheng and colleagues now analyzed four publicly available datasets that contained RNA sequencing data from hundreds of healthy and AD-affected brain cells. The Cheng lab received collaboration and help interpreting the data from Jae Jung, PhD, Chair of Infection Biology at Cleveland Clinic; neurologist James Leverenz, MD, formerly with Cleveland Clinic’s Lou Ruvo Center for Brain Health; and collaborators from Case Western Reserve University and the University of Nevada Las Vegas.

The team identified several transposable elements that were more highly activated in AD-affected brains that contained HSV-1 RNA relative to uninfected or healthy brains. They then tested HSV-1-infected brain cells to determine whether the identified transposable elements were activated, as well as the effects on neuroinflammation and accumulation of proteins associated with AD.

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The findings revealed a sequential outline that connects HSV-1 with hallmarks of AD:

An individual contracts HSV-1, or their latent HSV-1 infection becomes more active as a natural consequence of age. HSV-1 activates transposable elements such as those in the LINE1 (long interspersed nuclear element 1) subfamily. The transposable elements disrupt key genetic processes in the brain associated with an accumulation of tau and other AD-related proteins. The accumulated proteins contribute to inflammation and neurodegeneration.

A role for antiviral therapy?

The investigators then used artificial intelligence to analyze 80 million publicly available patient health records to evaluate whether individuals who were prescribed antiviral herpes medications were less likely to be diagnosed with AD later in life. The antiviral medications valacyclovir and acyclovir, both used for herpes, were each associated with a significantly reduced incidence of AD.

The researchers also found that treating a virus-infected human brain organoid model with these two antiviral drugs partially reversed the pathway of LINE1 dysregulation, mechanistically supporting what they observed in real-world patient data.

“These results further suggest potential relationships between HSV-1 infection and Alzheimer’s disease and provide two potential drug candidates that may provide treatment for a disease that currently has no cure,” Dr. Cheng says. “We hope our findings, if broadly applied, can also provide new strategies for treating other neurological diseases associated with herpesviruses or other viruses.”

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This research was supported by grants from the National Institute on Aging.