U.S. researchers were able to restore more than two hours of sleep per day in mice with Alzheimer’s-like changes. To do so, they did not need to remove the typical protein deposits in the brain or reduce their quantity. Instead, the intervention targeted overactive immune cells. The discovery could open up a new approach to treating sleep disorders in Alzheimer’s disease.

The Brain’s Immune System Can Become a Problem

Sleep problems in Alzheimer’s are far more than just an annoying side effect. Many people with the disease sleep restlessly, wake up frequently, or spend less time in important sleep stages. At the same time, changes in the sleep-wake cycle can become noticeable early in the course of the disease—sometimes even before memory problems are clearly pronounced. Why Alzheimer’s disease disrupts sleep so severely is not yet fully understood. A new study by scientists at the University of Kentucky in the U.S. now provides evidence of a previously underestimated mechanism: apparently, immune cells in the brain itself can contribute to throwing the natural sleep rhythm out of balance.

In experiments with mice, the research team succeeded in extending the animals’ sleep by more than two hours per day. Particularly noteworthy: the amyloid-beta protein deposits typical of Alzheimer’s remained intact. The researchers therefore did not need to remove them to achieve a significant improvement in sleep. The results thus bring an important question to the forefront: Could it be that, in Alzheimer’s, it is not only a matter of combating pathological deposits, but also of controlling the brain’s response to these deposits?

To understand the results, it is worth taking a look at what are known as microglia cells. These are specialized immune cells that perform an important protective function in the central nervous system. They recognize damaged cells, clear away cellular debris, and respond to potential threats. They also help maintain the biological balance in the brain. Without these cells, the nervous system would be significantly less able to respond to injuries and pathological changes. In Alzheimer’s disease, however, these protective mechanisms appear to become partially unbalanced.

A characteristic feature of the disease is amyloid plaques. These are deposits of protein fragments that accumulate outside nerve cells. They are among the best-known hallmarks of Alzheimer’s pathology and have been the focus of research for years. When microglial cells detect such deposits, they react to them. This reaction is thought to help eliminate potentially harmful structures or limit their effects. At the same time, however, the immune cells can release inflammatory signaling molecules, thereby triggering processes that extend beyond the immediate vicinity of the deposits.

The result could be a kind of overreaction by the brain: a protective mechanism that is actually intended to help increasingly impairs the normal function of the nervous system. This is precisely where the new study comes in. The research team wanted to find out whether the reaction of the microglial cells themselves disrupts sleep—or whether the sleep problems arise primarily from the amyloid deposits and direct damage to the nerve cells. The results suggest that the immune cells play a much more active role than previously thought.

What the Researchers Examined in the Mice’s Brains

For their study, the scientists used genetically modified mice that develop amyloid deposits. These animals serve as a model in Alzheimer’s research to investigate specific disease mechanisms under controlled conditions. For comparison, the team also included normal mice that undergo typical age-related changes but do not exhibit the same amyloid pathology. The researchers examined the animals at two different age stages: at six months and at 18 months. The younger animals showed the first signs of amyloid deposits, while the older animals exhibited a significantly more advanced burden of deposits.

Through this comparison, the scientists sought to answer two questions: Which changes are part of normal aging? And which ones occur specifically in connection with the Alzheimer’s-like disease? In doing so, they did not limit themselves to observing how long the animals slept. They also examined the brain’s electrical activity and the distribution of immune cells. To measure sleep, they used electroencephalography (EEG) and electromyography (EMG). The EEG records the brain’s electrical activity. The EMG measures the electrical activity of the muscles. Together, these methods make it possible to distinguish between wakefulness and different sleep stages.

In addition, the researchers used a specialized form of light-sheet microscopy. In this technique, biological tissue is prepared for examination and illuminated with a thin sheet of laser light. The images can be used to create three-dimensional representations that provide an overview of structures throughout the brain. In this way, the scientists were able to investigate where amyloid plaques are located and how microglial cells are distributed in the affected and adjacent brain regions. This was important because sleep is not controlled by a single brain region. Rather, different areas work together to regulate wakefulness, fatigue, and the various sleep stages.

Sleep Disturbances Appeared Early on – Even Though the Deposits Continued to Increase Later

One of the most surprising observations concerned the timeline of the sleep problems. The researchers had expected that the sleep disturbances would worsen as the amount of amyloid deposits increased. After all, in the mouse models used, the pathological deposits increase significantly over time. However, the measurements revealed a different picture. As early as six months of age, the animals with Alzheimer’s-like changes showed significant sleep deficits. By the time the animals were 18 months old and amyloid deposits had increased substantially, the observed sleep changes did not continue to worsen to the same extent.

The amount of plaques and the extent of sleep loss thus did not evolve in proportion to one another. The researchers describe this finding as a possible ceiling effect. This means that a certain degree of sleep disturbance was already reached relatively early on and did not increase correspondingly despite a further increase in plaques.

One possible explanation is that the immune system’s initial response to the developing plaques is particularly crucial. Once the microglial cells are activated and trigger processes that affect sleep, a large portion of the disturbance may already be established. This interpretation requires further investigation. However, the results suggest that early changes in the brain may be particularly important for the development of sleep problems.

Alzheimer’s Alters Sleep Differently Than Normal Aging

The study also revealed a difference between the effects of aging and the changes associated with Alzheimer’s-like pathology. Sleep consists of various phases that alternate multiple times throughout the night. Two important categories are REM sleep and non-REM sleep. REM sleep is characterized by rapid eye movements and distinctive patterns of brain activity. Vivid dreams occur particularly frequently during this phase. It is also associated with the processing of memories and other cognitive processes.

Non-REM sleep comprises several stages, including deep sleep. This phase is important for restorative processes and various processes related to learning, memory, and brain regulation. In normal mice, aging primarily affected REM sleep. In contrast, in animals with amyloid pathology, non-REM sleep was particularly impaired. This is an important distinction. It suggests that sleep problems associated with Alzheimer’s disease may not simply represent a more pronounced manifestation of normal age-related changes.

Instead, different biological mechanisms may be at play. However, the results do not mean that the sleep changes observed in mice can be directly applied to human sleep. Rather, they provide clues as to which processes should be examined more closely in future human studies.

The Crucial Experiment: 87 Percent of Microglia Cells Were Removed

To determine whether microglia cells are indeed responsible for the loss of sleep, the researchers performed a targeted intervention. They administered the drug pexidartinib—also known as PLX3397—to the mice. The drug blocks a signal via the so-called CSF1 receptor, which microglial cells need to survive. The treatment was administered over a period of 14 days. As a result, the number of microglial cells in the brain was reduced by about 87 percent. This step was crucial to the study. After all, a correlation between activated immune cells and sleep disturbances alone would not prove that the immune cells actually cause the sleep problems.

Through this intervention, the researchers were able to test how sleep changes when a large proportion of these cells is no longer present. The result was clear: the treated mice slept more than two hours longer per day. At the same time, non-REM sleep—the loss of which had previously been particularly pronounced—improved. The results suggest that microglial cells not only react to pathological changes but also actively contribute to the development of the sleep deficit. However, an important limitation must be noted: The researchers did not permanently remove the cells but instead investigated the effects of a temporary treatment. Furthermore, the experiment was conducted on mice, not on humans.

Sleep Improved Even Though the Amyloid Plaques Remained

It is particularly interesting that sleep duration improved without a corresponding reduction in amyloid deposits. This distinguishes the approach from strategies that primarily aim to reduce the amount of pathological protein deposits in the brain. The results suggest that at least some of the sleep disturbances can be influenced by a different mechanism: the immune response triggered by the deposits.

This does not mean that amyloid plaques are unimportant for Alzheimer’s disease or that their removal could not be beneficial in principle. The study does not answer these questions. Rather, it shows that the effects of the deposits on sleep cannot be explained solely by their mere presence. How the brain reacts to them and what processes are set in motion as a result also appear to be crucial.

This distinction could be of great significance for future research. Even if we succeed in reducing certain pathological deposits, this does not automatically mean that all the changes impairing the quality of life of those affected will disappear. Conversely, specifically targeting individual disease mechanisms could potentially alleviate certain symptoms without completely treating the underlying disease. It is precisely this possibility that makes this approach to researching sleep disorders in Alzheimer’s disease so interesting.

Why Poor Sleep Could Exacerbate a Vicious Cycle

Sleep is not merely a period of rest. During sleep, numerous processes take place that are important for brain function. These include information processing, the consolidation of certain memories, and the regulation of metabolism. Mechanisms involved in the removal of metabolic byproducts from the brain are also associated with sleep. If these processes are disrupted over an extended period, it can have consequences for brain function.

In Alzheimer’s disease, this could create a vicious cycle: pathological changes in the brain impair sleep. Poorer sleep, in turn, could alter conditions in the brain and disrupt processes that are important for its normal function. Whether this cycle actually accelerates the disease to a significant extent in humans has not yet been conclusively determined. The relationship between Alzheimer’s disease and sleep is complex and likely bidirectional.

Sleep problems can be an early accompanying symptom of the disease. At the same time, studies have linked poor sleep to an increased risk of cognitive impairment. However, it cannot be concluded from this that every sleep disorder causes Alzheimer’s disease or that improving sleep prevents the disease. Above all, the new study provides evidence of a possible biological link: the brain’s immune response could establish a connection between amyloid pathology and disrupted sleep. If this mechanism also plays an important role in humans, specifically targeting it could help treat some sleep problems in the future.

A study published in 2023 in the journal Molecular Neurodegeneration points in a similar direction. In that study, researchers were able to improve sleep in mice with Alzheimer’s-like changes by specifically activating certain nerve cells. At the same time, they observed changes in microglial cells, a reduction in amyloid deposits, and improvements in memory tests. When the animals were prevented from sleeping during treatment, some of these positive effects did not occur. This suggests that sleep itself played a role in the observed changes. Whether this approach can be applied to humans remains to be seen.

Why Microglia Cells Cannot Simply Be Permanently Deactivated

Despite the positive results, it would be wrong to already consider the extensive removal of microglia cells as a potential standard therapy. These immune cells perform numerous vital functions. They are involved in defending against pathogens, respond to tissue damage, and help maintain a functional environment for nerve cells. Removing them on a large scale could therefore also have undesirable consequences.

A long-term therapeutic approach would not only have to improve sleep but also ensure that the brain’s important protective functions are preserved. That is why the research team is exploring another possibility: Instead of eliminating microglia cells, one could attempt to specifically regulate their activity. The goal would be to mitigate an excessive inflammatory response without completely suppressing normal immune function. However, such an approach would only be therapeutically relevant once its efficacy and safety have been confirmed in carefully planned studies.

Can Existing Medications Help?

The researchers are investigating whether the activity of microglia cells can potentially be influenced through their cellular metabolism. Like other cells, microglia cells require energy. They alter their metabolism when they respond to inflammatory stimuli or need to adapt their functions. These changes could contribute to the immune cells entering a state in which they become overly active. The team is therefore examining, among other things, whether existing medications could influence this metabolism and thereby limit the harmful effects of the immune response.

The active ingredients under investigation include metformin, which is used to treat type 2 diabetes, and stiripentol, which is used for certain forms of epilepsy. However, the mention of these medications does not mean that their effectiveness against Alzheimer’s-related sleep disorders has already been proven. They are the subject of further research and should not be used on their own to treat Alzheimer’s or sleep problems based on these results.

Before such a use could be considered, it would first need to be clarified whether the active ingredients actually influence the desired biological processes, whether they improve sleep quality, and what risks would be associated with them. Subsequently, clinical trials would be necessary to determine whether the results also hold true in humans.

EEG as a Potential Tool for Earlier Detection

The study may be of interest not only for the development of therapies. It also provides evidence that Alzheimer’s-like changes are reflected in certain patterns of electrical brain activity. To this end, the researchers examined the animals’ EEG signals more closely. Using mathematical methods, they decomposed the measured activity into different components. This allowed them to identify changes related to the excitability and coordination of neural networks.

In mice with amyloid pathology, they found, among other things, evidence of increased excitability in the cerebral cortex and altered coordination of activity between neural networks. Such patterns could help to more accurately detect changes in brain function in the future.

The EEG has a practical advantage in this regard: It is relatively inexpensive, does not require surgery, and can be performed repeatedly. In the future, wearable devices could also enable measurements outside of specialized clinics.

The researchers therefore see potential in investigating EEG measurements as additional biomarkers. A biomarker is a measurable characteristic that provides clues about a biological state or a disease. However, based on current knowledge, an EEG alone is not sufficient for reliable early detection of Alzheimer’s disease. The signatures observed in the study must first be validated in human trials. Only then can it be determined whether they could serve as a useful supplement to established diagnostic procedures.

What the Results Mean for People with Alzheimer’s, and What They Don’t

For those affected and their families, the idea of being able to restore lost sleep is understandably of particular interest. Sleep problems can significantly impact daily life, make it difficult to concentrate, and also complicate the care of people with dementia. The new study provides a scientifically grounded approach to better understanding some of these problems. It shows that sleep could be significantly improved in an animal model, even though the amyloid deposits remained. However, there is no evidence yet that this effect can be achieved in humans.

It is also unclear whether improved sleep would have a lasting impact on memory function or other symptoms of Alzheimer’s disease. The study primarily examined sleep and electrical brain activity. It does not demonstrate a cure for the disease or a reversal of the underlying neurodegenerative process. The results should therefore not be interpreted as a call to change existing medications or to take new drugs on one’s own. Their value lies primarily in identifying a potential mechanism that further research can investigate in greater detail.

A New Perspective on Alzheimer’s Disease

Alzheimer’s research has long focused heavily on pathological protein deposits and changes in nerve cells. These aspects remain important. However, the new study highlights that the immune system’s response may also play an independent role in certain symptoms. Microglia cells could act as a kind of mediator between amyloid deposits and the regulation of sleep. If their activity becomes unbalanced, it could influence processes that extend far beyond the immediate vicinity of the deposits. The possibility of improving sleep without altering the amount of amyloid thus broadens our understanding of the disease. It suggests that different symptoms may be influenced by different biological mechanisms.

The next step is to determine whether the observed processes can also be detected in the human brain and whether targeted regulation of microglial cells actually provides therapeutic benefit. If successful, this could eventually lead to a new approach for alleviating sleep disorders in Alzheimer’s and potentially improving the quality of life for those affected. Until then, the study’s most important finding remains a scientific one: In the mouse model, it was not solely the amount of amyloid deposits that was decisive for sleep loss. The response of immune cells also played a significant role—and could be experimentally modulated. The study thus points to a promising avenue of research, but does not yet represent a fully developed treatment. Further studies are needed to determine whether sleep in people with Alzheimer’s can be improved in a similar way.