Introduction to Alzheimer’s Disease

Alzheimer’s disease (AD) was discovered by German neurologist Alois Alzheimer, who noticed an unusual aggregation of proteins, currently known as amyloid plaques and tau tangles, in the brain of a woman who had experienced memory loss, difficulty speaking, disorientation, and hallucinations (Breijyeh & Karaman, 2020). This neurodegenerative disease can affect memory, thinking, and behavior and is one of the leading causes of dementia in people over 65 years old (“2024 Alzheimer’s Disease Facts and Figures,” 2024). The disease itself causes physical damage and changes to the brain, including the development of the characteristic amyloid plaques and tau tangles and a significant reduction in brain volume (Traini et al., 2020). Presentation of symptoms can vary, ranging from memory defects to a reduction in cognitive ability and difficulty moving or controlling movements (Graff-Radford et al., 2021).

Many risk factors are associated with the disease. Aging is the most common, as it is often associated with the prevalence of a number of diseases and comorbidities, a less effective immune system (Palacios-Pedrero et al., 2021) and reduced cognitive function (Eshkoor et al., 2015). Genetics can also increase risk, as specific mutations can drastically affect not only the likelihood of an individual having AD but also dictate the severity and onset of the disease (König & Stögmann, 2021). Positive and negative lifestyle changes such as diet, sleep, exercise and other influences have been linked to and can influence the occurrence and severity of AD (Dhana et al., 2020). In having many potential contributing factors, AD is very complex with no universal treatment or cure. Therefore, understanding the underlying biological, molecular and behavioral characteristics behind AD progression allows for many different pathways to approaching the study and treatment of AD.

Characterization and Basic Biology of Alzheimer’s Disease

The primary pathology driving AD progression is a toxic buildup of the proteins tau and amyloid beta (Aβ) to form neurofibrillary tangles and amyloid plaques, respectively. Tau is a protein that typically helps stabilize the structure of neurons by binding to microtubules, which helps with neuronal shape and neuronal signaling (Mietelska-Porowska et al., 2014). However, when these proteins are abnormally hyperphosphorylated, tau then aggregates into insoluble clusters (Opland et al., 2023). These clumps can lead to a decrease in cognitive function by disrupting the microtubule structure of neuron cells and further contributing to AD pathology (Teravskis et al., 2020).

While tau tangles are one component of AD pathology, much of AD research has traditionally focused on the buildup of amyloid plaques. These plaques are composed of Aβ protein, a fragment of the larger amyloid precursor protein (APP) as a result of enzymatic cleavage (Zhou et al., 2011). APP typically helps with cell-to-cell communication in neural tissue that needs to be cleaved by the enzyme secretase to break down into smaller pieces. Although this process regularly occurs in the brain, it can become problematic when these fragments release Aβ peptides which are prone to misfolding and aggregation. These small clusters become larger and more dense to form insoluble plaques that disrupt cell function and interfere with neuronal connectivity and communication (Soto & Pritzkow, 2018). They can also signal an immune response, resulting in inflammation and potential damage to the surrounding neurons or other brain cells (Everett et al., 2024). Plaques can also occur in and weaken the walls of blood vessels in the brain, making them more prone to ruptures that can lead to bleeding in the brain, known as hemorrhagic stroke (Smith & Greenberg, 2009). Therefore, the overall health and structure of the brain can be greatly compromised by the characteristic pathology seen in AD.

Tau tangles first start to aggregate in parts of the brain which involve memory, such as the hippocampus. Then as disease severity increases it spreads throughout the brain causing difficulty with memory and functional abilities (Metaxas & Kempf, 2016). Amyloid plaques start to aggregate in the basal, temporal, and orbitofrontal regions of the brain during the early stages of AD, which may present with traditional symptoms such as forgetfulness, difficulty completing familiar tasks, challenges solving problems, confusion with time, and poor judgment (Breijyeh & Karaman, 2020). As the disease progresses, plaques spread to the neocortex, hippocampus, amygdala, diencephalon, and basal ganglia causing more severe symptoms, such as amnesia (Tiwari et al., 2019). More critical cases show a spread all the way to the brainstem which includes additional symptoms, such as severe communication issues, significant behavioral changes, and loss of mobility (Ossenkoppele et al., 2022). Given AD has an impact on all areas of the brain, it is very difficult to understand and effectively target the different facets of the disease. Ultimately, understanding these characteristics and the regions of the brain impacted by AD are crucial to building strategies to address the disease in order to improve symptom management or alter characteristic progression.

The Evolution of Alzheimer’s Disease Treatments

As there currently is no cure for AD, research and development is focused on new technologies for diagnosing AD and advancing potential therapeutics. Early forms of treatment include cholinesterase inhibitors, which increase the availability of acetylcholine in neuromuscular junctions to reverse impaired cholinergic pathways (Hampel et al., 2018). Acetylcholine is a neurotransmitter that enables muscle action, learning and memory, so a limited supply can cause deterioration of neurons in the brain (Sam & Bordoni, 2024). More specifically, a decrease in the amount of acetylcholine availability in the hippocampus, as seen in AD cases, could increase the chance of cognitive decline (Haam & Yakel, 2017; Sun et al., 2022).

Current treatments still employ these approaches, but many new forms target additional facets to mediate specific symptoms or pathways driving AD. Tau and amyloid targeting treatments focus specifically on inhibiting the production of either tau or amyloid plaques in the brain. Monoclonal antibodies are one subset of these targeting treatments that can intervene through specific mechanisms of the disease pathway to halt or slow disease progression. One example is Lecanemab, which focuses on targeting and clearing Aβ protofibrils, the clusters of proteins that form before the development of fully mature fibrils and can cause structural damage to neurons (Thangwaritorn et al., 2024). NMDA (N-methyl-D-aspartate) receptor inhibitors are a class of drugs that may treat memory loss and brain damage associated with Alzheimer’s disease (Thangwaritorn et al., 2024). This works by aiding the process of neurotransmission, allowing the flow of calcium and potassium through the membrane to stimulate neural firing which allows for effective functioning of neurons and better cognitive function.

In addition to these pharmaceutical interventions, lifestyle-based changes can have a beneficial impact on the quality of life of the patient allowing for greater satisfaction and well-being. As a result, therapeutics often differ from case to case and can include combination therapies and the integration of non-pharmaceutical options such as changes to diet, exercise, and sleep. Sleep, for example, can be adapted and can have a more universal reach so that all can benefit. While these therapeutic advancements can certainly help mediate a patient’s condition, these therapies do not constitute a cure and further attests to the complexity of AD progression and the need for further investigation and understanding.

The Biology of Sleep

Sleep is a necessary biological process that helps direct proper function and maintenance of the body and mind. During a period of sleep, the brain progresses through various stages (Reddy & Van Der Werf, 2020). First is a period of three non-rapid eye movement (NREM) sleep stages: N1, N2, and N3. N1 marks the transition from wakefulness to sleep and is followed by N2, a transition stage from a light sleep state into deeper sleep. Characteristics of N2 include bursts of rapid rhythmic brain-wave activity called sleep spindles accompanied by decreasing body temperature and heart rate. Stage N3 is considered a period of deep sleep marked by slowed heart rate and breathing as well as delta brain wave activity, which is the slowest type of brain wave that aids memory consolidation and cognitive restoration. Tissue repair, growth and cell regeneration also typically occur during this period. Rapid Eye Movement (REM) sleep follows this, where vivid dreams occur, brain activity increases, and muscles relax. This stage is also really important for cognitive function and memory, as it is often associated with improvements in concentration, decision-making, and overall clarity (Boyce et al., 2016). REM also supports consolidation, growth, and connectivity between neurons in the brain, allowing for better development of memory and other cognitive functions (Roffwarg et al., 1966).

Sleep is directed by circadian rhythms, which are often referred to as the “biological clock.” Periods of sleep are often coordinated with other biological rhythms such as hormone production and body temperature, which all contribute to bodily homeostasis (Cable et al., 2021). For example, hormones help with the body’s metabolism, growth, development, mood, behavior, and maintenance of a stable internal environment. Body temperature can also significantly impact a multitude of reactions and processes occurring within the body (Hiller-Sturmhöfel & Bartke, 1998). Additionally, cerebrospinal fluid more readily flows in and out of the brain during periods of sleep, helping to remove toxins and damaging proteins from the brain (Fultz et al., 2019). Sleep is, therefore, an important part to the synchrony of a number of biological processes to maintain a healthy state through the body.

Production of the sleep-promoting hormone melatonin, which is closely linked with light exposure, also plays several important roles in bodily health (O’Gara et al., 2021). Melatonin has been shown to help individuals fall asleep faster, increase length of sleep, and improve sleep quality. In addition, it has antioxidant properties and can help with bodily homeostasis to regulate other hormones associated with stress response, such as increased heart rate, rapid breathing, and release of adrenaline. Good sleep hygiene, such as a consistent sleep schedule, limited screen time and comfortable sleep environment, can regulate and enhance melatonin production, perpetuating regular sleep cycles and improved quality of sleep. Inversely, dysregulated sleep, which can be identified via abnormal sleep duration, efficiency, quality or timing, can have a strong biological impact on the brain and the body, including altered melatonin metabolism, neurotransmitter imbalances, and disrupted homeostasis.

Sleep disturbances also often accompany conditions like heart failure and cardiovascular disease, diabetes, urological symptoms, chronic pain and can impact cognitive function including attention and memory (O’Gara et al., 2021). Decreased attention and slower reaction times are directly linked to sleep deprivation (Xin et al., 2022). Sleep deprivation occurs when a person consistently gets less sleep than the amount needed for optimal function. This threshold can vary from person to person and, when persistent, can develop into chronic sleep deprivation. Chronic sleep deprivation showed a strong correlation with reduced attention, worsened working memory, and decreased performance in psychomotor tasks (García et al., 2021). Adequate sleep is therefore essential for regulating vital bodily function, supporting cognitive and emotional health, and preventing issues such as impaired memory.

Sleep’s Correlation with Alzheimer’s Disease

Compared to healthy individuals, AD patients typically have a number of sleep-related issues such as having trouble falling or staying asleep, producing sleep-related hormones and regulating sleep patterns. When sleep-wake activity was monitored using sleep measurement devices, such as an EEG, sleep disturbances occurring in REM caused latency and reduced sleep efficiency correlated with both amyloid and tau pathologies (Musiek et al., 2015). Additional studies in both AD patients and mouse models have revealed disrupted circadian rhythms and light-dark sleep cycles (Weigel et al., 2023). As previously mentioned, irregular sleep–wake cycles can alter melatonin secretion and diminish the benefits of a regular circadian rhythm. In line with these findings, severity of AD neuropathology is inversely correlated with melatonin levels (Cardinali et al., 2002). This relationship between AD and melatonin production could therefore be a potential tool in understanding and approaching AD diagnostics because it is easier to detect changes in melatonin levels through simple blood tests or urine analysis when compared to analyzing a patient through medical assessments and brain imaging. In addition, REM and slow-wave sleep behavior are also significantly reduced in AD patients, leading to lower sleep quality. These observed changes in sleep patterns in participants with early clinical symptoms can show progression of AD pathology before significant cognitive decline (Lucey et al., 2019).

Sleep as a Potential Risk Factor for Alzheimer’s

As the progression of AD has an impact on sleep, it is worth noting this relationship is bidirectional, as sleep may have its own role in disease risk and onset to perpetuate a feed-forward cycle and drive disease progression. In animal models, sleep deprivation is linked to increased Aβ plaque accumulation in brain pathology (Musiek et al., 2015). In observational studies, individuals with sleep problems had a higher prevalence of AD, cognitive impairment, and preclinical AD, where there is a presence of tau tangles and amyloid plaques with no additional identifiable symptoms (Brenowitz & Yaffe, 2022; Bubu et al., 2017). Cognitive function decreases when individuals get less than 4.5 hours of sleep on consecutive nights, and AD risk increases when cognitive function progressively diminishes (Lucey et al., 2019). As a prominent risk factor for AD, age is linked to altered sleep patterns and disturbances which suggest changes in circadian function. This can lead to increased wakefulness at night, longer sleep latency, more nocturnal awakenings, and increased daytime sleep in patients, all which can lead to a loss of day-night rhythm (Musiek et al., 2015). As a result, acute sleep deprivation can cause slowed down reaction times (Van Dongen et al., 2003), reduced attention span (Thomas et al., 2000), impaired decision making (Killgore et al., 2006), and a decline in language and communication skills (Harrison & Horne, 1998). Given the importance of sleep on our health and brain function, it may be even more important for the elderly to obtain proper rest as they are more heavily impacted by and most at risk for developing AD.

Modulation of Sleep for Memory Enhancement

In addition to supporting overall health and biological homeostasis, sleep has a significant role in memory and cognitive function. Regulating or modifying sleep habits therefore may not only combat established or developing cognitive deficits, but can also have the capacity to improve memory and mental function. For example, taking naps to frame periods of sleep around learning can be used to enhance memory. While naps or short periods of sleep before learning can increase alertness and cognitive performance, taking a nap after can help to consolidate memory (Cousins et al., 2019). Targeting and manipulating different parts of memory processing during sleep can also be a useful tool. The use of auditory cues, smells, and applying electrical currents to stimulate the brain during sleep can serve as a cognitive enhancer to provide optimal conditions to augment memory capacities. For example, odor has been shown to increase slow wave activity during sleep to facilitate memory (Diekelmann, 2014). Targeting or focusing on specific brain waves and sleep stages can also allow for better absorption of memory and events, as slow oscillations, sleep spindles, and hippocampal ripples are closely linked to memory consolidation (Adamantidis et al., 2019). The stimulation of slow oscillations during sleep has proven to not only enhance the memorization of previously learned memories but can help people retain new information more effectively. For example, individuals were able to learn more new words and recall pictures after electrical slow oscillation stimulation (Antonenko et al., 2013). In animal studies, it has been shown that the suppression of ripples impairs memory. Unfortunately, sleep spindles and ripples in the hippocampus are harder to manipulate externally, so the extent to which this could be used to enhance memory in humans is still unknown due to its invasive nature (Diekelmann, 2014).

Due to the negative effect that sleep deprivation has on cognitive function (Van Dongen et al., 2003), an increase in sleep quality may have an opposite effect. Since manipulation of sleep has potential applications for enhancing cognitive performance and memory in healthy individuals, it therefore could be particularly beneficial for those with memory deficits, such as with patients suffering with AD. These methods could show an increase in memory consolidation and cognitive function that could be lost as a combined result of aging and disease progression. This connection may also lead to future beneficial use in clinical trials.

Benefits of Melatonin for Patients with Alzheimer’s Disease

As stated previously, melatonin levels are decreased in AD patients, suggesting a disruption in melatonin production or regulation in AD that may result in the identifiable circadian rhythm disturbances (Nous et al., 2021). While this has potential for identifying individuals at risk for or currently with early-stage AD, a supplementation of melatonin could be used as a potential therapeutic method to support these patients. It is commonly available for use to help regulate and improve sleep quality and timing, and therefore could easily be adapted for individuals with AD. Additionally, the use of melatonin has been linked to a reduction in Aβ production in AD patients and mouse models, potentially altering progression of AD disease pathology. In the same study, melatonin was shown to inhibit the creation of Aβ plaques, prevent the formation of fibrils, and protect neurons from the toxins that excrete from the protofibrils (Li et al., 2020). This supplementation of melatonin has been shown to stem Aβ accumulation, neurodegeneration, inflammation, and memory impairment in AD animal models and patients (Cardinali, 2019). Adding melatonin to a daily routine therefore is a low-risk, affordable, and easily adapted lifestyle change that could help build the importance of sleep and its benefits into the clinical world for patients with AD and other neurodegenerative diseases.

Conclusion

Sleep is a dynamic biological process critical to an individual’s health and cognitive function with significant relevance to AD. While AD gives rise to atypical sleep patterns and could be an indicator of possible AD pathology, disordered sleep can increase risk and severity of the disease. Sleep isn’t commonly noted as a formal treatment or core cause of disease, but existing research establishes that improvements in sleep could have a protective or preventative effect on cognitive function and disease progression. Additional methods and advancements can be used to not only improve sleep, but also have the potential to mediate cognitive and pathological symptoms. For example, outside stimulants such as auditory cues, smells, and applying electrical currents or taking supplementation, such as melatonin, can significantly improve the quality and biological effects of sleep. This highlights the relevance for sleep intervention as a treatment strategy to not only improve quality of life in AD patients but also identify specific disease mechanisms to inform future research and clinical approaches. Ultimately, developing research in this field could lead to breakthroughs regarding how sleep can help to uncover and better understand progression of AD and other diseases that may share this connection.

Acknowledgements

I would like to thank Maria Iuliano for her guidance and mentorship on this project.

Conflicts of Interest

The author declares that there are no conflicts of interest regarding the publication of this article.