Clearance mechanisms of the glymphatic/lymphatic system in the brain: new therapeutic perspectives for cognitive impairment

Abstract

The glymphatic/lymphatic system of the brain has been an important discovery in the field of neuroscience in recent years. As the "waste clearance network" of the central nervous system, it clears metabolic products and neurotoxic substances through the cerebrospinal fluid–interstitial fluid circulation, which is crucial for maintaining the homeostasis of the intracerebral environment and plays important roles in learning, memory and other advanced cognitive functions. The glymphatic/lymphatic system is crucial for the clearance of beta-amyloid and tau proteins, and thus the abnormal function of this system has been confirmed to be closely related to the pathological mechanisms of various diseases associated with cognitive impairment, such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia. The physiological function of this system is influenced by a variety of factors, especially when it is relatively active during sleep. The application of noninvasive imaging techniques to assess glymphatic/lymphatic system function has facilitated the development of clinical research. Therefore, a focus on the role of the cerebral glymphatic/lymphatic system in cognitive impairment and an understanding of its relationship with cognitive impairment from a new perspective are of great scientific and clinical importance.

Introduction

Lymphatic vessels operate in parallel with the vascular system and constitute the second circulatory system in the body; the system is as important as the vascular system and is the main way in which tissues eliminate excess fluid and protein (Fahmy et al. 2021). It is necessary to maintain tissue homeostasis, and the distribution density of lymphatic vessels is often related to the metabolic rate of the tissue. In recent years, neuroscientists have become increasingly interested in the glymphatic/lymphatic system of the brain. In particular, the discovery of the meningeal lymphatic vessels and glymphatic system has added to the understanding of brain structure and function, allowing researchers to reconsider the blood–cerebrospinal fluid (CSF) barrier, CSF circulation, fluid flow and metabolic pathways in brain tissue (Ding et al. 2023). The role of the glymphatic/lymphatic system in cognitive impairment is increasingly recognized, providing new research ideas in the field of cognitive disorders, and this system may be a promising potential therapeutic target. This paper aims to review the structure and function of the glymphatic/lymphatic system, summarize recent research progress in the field of cognitive disorders, and look forward to future research directions and clinical application prospects.

The glymphatic/lymphatic system in the brain

The glymphatic/lymphatic system in the brain mainly transports nutrients and neuroactive substances and clears endogenous and exogenous metabolites (Ding et al. 2023; Gouveia-Freitas and Bastos-Leite 2021). It is an important fluid flow system that maintains the homeostasis of the brain environment. Traditionally, metabolites produced by the brain tissue enter the CSF and are discharged into the venous system through the CSF circulation to achieve metabolic renewal. However, the discovery of the glymphatic system and dural lymphatic vessels has led scholars to gain a new understanding of the cerebral glymphatic/lymphatic system (Sun et al. 2018; Alves de Lima et al. 2020; Ding et al. 2021; Li et al. 2022a).

Perivascular space

Before elucidating the specific mechanism of glymphatic clearance function, an understanding of the perivascular space (PVS) in the brain, which provides a channel for the flow of CSF within the glymphatic system, is necessary (Tian et al. 2022; Wardlaw et al. 2020; Sepehrband et al. 2021). On the surface of the cerebral cortex, the cerebral arteries continue into the pial meningeal arteries and travel through the subarachnoid and subpial spaces containing CSF. As the pial arteries dive into the brain parenchyma, they transform into penetrating arteries. In this process, a space surrounded by the pia between the blood vessels and the brain parenchyma is formed that is called the PVS, also known as the Virchow–Robin space (VRS) (Brown et al. 2018). The PVS is filled with CSF and can be seen as an extension of the subarachnoid space. With the branching of penetrating arteries into arterioles and capillaries, the PVS gradually narrows and eventually disappears. The inner wall of the PVS is composed of vascular cells, and the outer wall is composed of astrocytes (Yao et al. 2023). As an important part of the cerebral glymphatic system, the PVS functions to support the structure and transport substances.

Glymphatic system

Cserr et al. initially proposed the presence of the glymphatic “perivascular” system and interstitial fluid (ISF) bulk flow, and in a subsequent study using a horseradish peroxidase infusion, perivascular horseradish peroxidase was detected in rat brains at 4–8 h postinjection (Cserr and Ostrach 1974; Cserr et al. 1977). Injecting isotopes of different molecular weights into the caudate nucleus of rats resulted in similar clearance rates for all the molecules, despite different diffusion coefficients, suggesting perivascular drainage via bulk flow (Cserr et al. 1981). Studies have shown that dogs and cats also have perivascular clearance systems (Rennels et al. 1985). Despite the above evidence, the hypothesis of CSF perivascular flow has been shelved for more than two decades because of limited confirmation by other researchers and technical limitations.

Iliffe and colleagues first described the glymphatic system in 2012 (Iliff et al. 2012). The term “glymphatic’’ was coined to combine “glia” and “lymph” because of the important role of astrocytes and their similar function to that of peripheral lymphatics (Iliff et al. 2012). However, previous research seems to support the concept of the glymphatic system. Because CSF flows from the subarachnoid space into the cervical lymph system in the nasal cavity, in the orbit, and in the region of the jugular foramen, we conclude that an important component of CSF circulation is lymphatic drainage. The recently described glymphatic system is a missing component of the previously outlined CSF flow route (Mezey and Palkovits 2015). The operation of the glymphatic system relies on the bulk flow of CSF through the spaces that create it and cleanses the brain (Jessen et al. 2015). The glymphatic system is an important part of the central lymphatic system and is responsible for the main process of substance exchange and drainage between CSF and ISF. The glymphatic flow can be divided into three main stages (Natale et al. 2021; Szlufik et al. 2024). First, CSF is produced mainly in the choroid plexus and flows from the subarachnoid space to the brain parenchyma (Hablitz and Nedergaard 2021). This flow occurs through periarterial spaces (also known as Virchow spaces) (Mestre et al. 2017). Subsequently, AQP4 plays a crucial role in the second stage (Benveniste et al. 2019). AQP4 is a high-density water channel expressed on the endfeet of astrocytes. This water channel mediates the flow from the periarterial spaces to the brain parenchyma, where the CSF from the interstitial space mixes with the ISF, and substances dissolve (Mezey and Palkovits 2015). In the third stage, the ISF exits the brain through the perivenous spaces and subsequently enters the peripheral lymphatic system (Fig. 1).

Fig. 1.

Schematic representation of the glymphatic system. The working mode of the glymphatic system/meningeal lymphatic vessels: the subarachnoid CSF enters the deep part of the brain along the periarterial space, flows into the cerebral space (CSF → ISF) mediated by AQP4, and pushes the cerebral ISF back into the subarachnoid space (ISF → CSF) through the perivenous space

Despite some progress in our understanding of the glymphatic system, several key challenges remain in the field. Is the glymphatic system limited to the flow of fluid terminally regulated by astrocytes in the PVS, or does it form a more complex network with meningeal lymphatic vessels? How do the glymphatic system, meningeal lymphatic vessels and blood–brain barrier work together to maintain homeostasis in the brain? Additionally, whether the polar distribution of AQP4 in astrocytes is the core regulatory target of the glymphatic system and whether its imbalance directly leads to a decrease in clearance efficiency remain unclear.

Olfactory/neck lymphatic drainage pathway

The discovery of the glymphatic system explains how metabolites in the brain parenchyma are transported out of the brain parenchyma through the exchange of CSF with ISF. However, harmful metabolites expelled from the brain parenchyma remain in the CSF. The traditional view is that CSF leaves the subarachnoid space and enters the dural venous sinus through arachnoid granulations (Plog and Nedergaard 2018). Later studies revealed that the subarachnoid space extends along the olfactory tract through the cribriform plate and eventually extends into the nasal submucosa near the olfactory nerve (Liu et al. 2012; Spera et al. 2023). When CSF flows into the nasal cavity, the lymphatic vessels responsible for the drainage of CSF surround the olfactory nerve and follow it through the cribriform plate (Norwood et al. 2019; Chae et al. 2024). The nasal submucosa along the nasal cavity can be reached by connecting the nasal lymph system and the ethmoidal lamellar lymphatic vessels. Eventually, they travel through the lymphatic network to the lymph nodes in the neck (Norwood et al. 2019; Chae et al. 2024). This pathway to the nasal lymph system forms an important part of the CSF lymph outflow pathway (Norwood et al. 2019; Chae et al. 2024; Ma et al. 2017). Using techniques such as tracer tracking, multiple studies have conclusively demonstrated the existence of this pathway and clearly identified it as an important pathway for CSF drainage, through which approximately 15% to 30% of the CSF can be eliminated (Kida et al. 1993; Koh et al. 2005). Recently, researchers have also reported the use of tracers along several cranial nerves after intraventricular perfusion in mice (Ma et al. 2017).

Meningeal lymphatic vessels

Two 2015 studies identified lymphatic vessels located in the dural membrane that pass through holes at the base of the skull and into deep cervical lymph nodes, closely linking the brain to the peripheral lymphatic system (Aspelund et al. 2015). Later, the meningeal lymphatic vessels were shown to be functionally connected to the glymphatic pathway and constitute a major route by which CSF is drained to the cervical lymph nodes (Formolo et al. 2023). Louveau and colleagues identified a network of vessels in the superior sagittal and transverse sinuses that expressed various lymphatic endothelial cell markers, such as the lymphatic endothelial cell hyaluronan receptor 1, PROX1 protein, and vascular endothelial cell growth factor receptor 3, thus confirming that these vessels were lymphatic vessels (Louveau et al. 2015). The lymphatic network not only exists around the venous sinus but is also widely distributed around the intracranial arteries and cranial nerves, with vessels flowing out of the skull along the cranial nerves or arteriovenous vessels. Meningeal lymphatic vessels collect and drain brain interstitial fluid and deep cervical lymph nodes. Like those of peripheral lymphatic vessels, their function is regulated by VEGFR3 (Aspelund et al. 2015; Antila et al. 2017).

The discovery of the meningeal lymphatic system has improved the traditional understanding of lymphatic drainage in the central nervous system, and it is expected to be a therapeutic target for some central nervous system diseases. However, the results obtained thus far are far from complete. For example, how the meningeal lymphatic vessels and the glymphatic system work together to accomplish waste removal and the mechanisms of their interaction are not yet clear, the distribution of meningeal lymphatic vessels (such as the differences between humans and mice) has not been accurately mapped, and a series of problems need to be solved. With the development of basic and clinical studies, the anatomy, growth and aging of the meningeal lymphatic system and its important physiological functions in maintaining cerebral homeostasis will be further clarified. Future studies should explore the relationships between central nervous system diseases and meningeal lymphatic vessels more carefully.

Factors influencing the glymphatic/lymphatic system in the brain

The glymphatic/lymphatic system can clear metabolic waste from the brain, and thus studying the factors affecting glymphatic/lymphatic circulation is beneficial for reducing the accumulation of cellular waste and maintaining the normal function of the brain. Researchers have identified several potential drivers of glymphatic/lymphatic transport, such as respiration (Helakari et al. 2022), vasomotion (Veluw et al. 2020), and CSF production and turnover (Rasmussen et al. 2018; Smets et al. 2024). Respiration and arterial pulsation are currently thought to be the main driving forces of fluid flow in the glymphatic/lymphatic system (Li et al. 2022).

Arterial pulsation

Cardiac pulsatility has been identified as the main force driving the flow of CSF around arteries (Fultz et al. 2019). A previous study revealed that CSF bulk flow in the PVS is pulsatile, with the same frequency as the heart cycle and in the same direction as blood flow (Iliff et al. 2012; Bedussi et al. 2018). One study used two-photon imaging in vivo to simultaneously measure CSF flow speeds and record cardiac and respiratory cycles (Mestre et al. 2018). These results are highly consistent with the fluid delivery mechanism of perivascular pumping, where vascular wall dynamics directly drive pulsatile CSF bulk flow in the PVS (Mestre et al. 2018). A previous study revealed that cardiac pulsation was the primary source of convective movements in the area around arteries, whereas respiration appeared to play a convective role in the area around the veins (Kiviniemi et al. 2016). Thus, the cardiac cycle and respiratory cycles may contribute to different aspects of the glymphatic pathway. After unilateral internal carotid artery ligation, the degree of arterial pulsation decreased by approximately 50%, and the CSF-ISF exchange rate decreased (Iliff et al. 2013). In animal studies, the adrenergic agonist dobutamine significantly increased arterial fluctuations, thereby promoting perivascular CSF-ISF exchange (Iliff et al. 2013). These results suggest that arterial pulsation promotes CSF flow in the glymphatic system through the PVS (Ding et al. 2023).

Respiration

Compared with the positive pressure effect of arterial pulsation on driving CSF to enter the brain parenchyma, respiratory movement mainly affects venous contraction and exerts a "suction" effect on the ISF. Respiratory movement can cause venous dilation and collapse, resulting in the periodic narrowing and widening of the venous PVS and promoting the outflow of ISF from the brain parenchyma. Kiviniemi et al. confirmed by magnetic resonance electroencephalography that respiratory movement drives CSF flow in the glymphatic system by affecting the venous PVS (Kiviniemi et al. 2016). Respiratory movement affects not only the direction but also the velocity of CSF flow. Inspiration increases the CSF flow rate, and breath holding significantly inhibits CSF flow. Inspiration increased the CSF flow rate, and breath holding significantly inhibited CSF flow. The choroid plexus continuously produces CSF, creating a driving force that directs fluid from the ventricular system into the subarachnoid space. When breathing deeply, each inhalation causes a high flow of CSF, and breath holding suppresses it, which may be associated with lower chest pressure when inhaled. Recent studies have shown that continuous positive airway pressure (CPAP) can increase the flow rate of CSF at the skull base and enhance local glymphatic transport (Ozturk et al. 2023). The CPAP-induced increase in the CSF flow rate was related to increased intracranial pressure. These findings suggest that CPAP may have therapeutic benefits in maintaining glymphatic function.

Sleep

Sleep has been identified as a key factor affecting cerebral glymphatic/lymphatic function and the expansion of CSF exchange (Xie et al. 2013; Benveniste et al. 2019 Apr; Reddy and Werf 2020; Ciurea et al. 2023; Licastro et al. 2024). During sleep, the interstitial space volume increases by approximately 60%, resulting in reduced convective resistance in association with an increase in CSF glymphatic influx of approximately 95% (Xie et al. 2013). Through two-photon microscopic imaging technology, the volume fraction of tissue space during natural sleep and anesthesia-induced sleep was 22–24%, which was noticeably greater than that during normal sleep (13–15%) (Xie et al. 2013). The high-volume fraction indicates a decrease in flow resistance in the ISF, and thus the brain glymphatic circulatory function increases significantly during sleep or anesthesia. In addition, ISF solutes are cleared twice as fast during sleep (Xie et al. 2013), whereas sleep deprivation significantly reduces glymphatic activity (Liu et al. 2017a). This finding is consistent with the traditional theory that sleep helps eliminate metabolic waste and maintain homeostasis. Glymphatic influx and clearance show an endogenous circadian rhythm that peaks in the middle of the rest of the period in mice (Hablitz et al. 2020). The increase in glymphatic system flow and the increase in the ISF volume occurred primarily during the more frequent occurrence of delta waves during sleep, which coincided with the nonrapid eye movement (NREM) phase (Xie et al. 2013). Previous human studies have shown that CSF inflow increases at the NREM 3 stage, when nutrients and blood flow to the brain decrease (Fultz et al. 2019). Lymphatic blood flow is highest in NREM 3 and decreases with decreasing sleep depth (Gao et al. 2023).

Norepinephrine is believed to be the key regulator of the transition between sleep and wakefulness (Jessen et al. 2015). It is the main stimulatory neuromodulator responsible for increasing neuronal activity and collecting and processing sensory information (Berridge et al. 2012). The norepinephrine level is higher during wakefulness and lower during sleep. In the brains of adult mice, the administration of a mixture of adrenergic antagonists resulted in reduced activity of the glymphatic/lymphatic system, similar to the state of sleep (Xie et al. 2013). In turn, rapid stimulation caused the release of norepinephrine, which led to a reduction in the intercellular space in the parenchyma of the brain. Subsequent studies showed that injecting an adrenergic receptor antagonist into the CSF inhibited central norepinephrine transmission and increased the volume of the ISF and the activity of the cerebral glymphatic/lymphatic circulation (Murtazina et al. 2021). Recent findings suggest that NE oscillations induced by the coeruleus are key drivers of slow vasomotor activity, which in turn promotes glymphatic clearance during natural sleep (Hauglund et al. 2025). These findings suggest that norepinephrine, an important neurotransmitter in the brain that regulates arousal, also plays a crucial role in the glymphatic/lymphatic circulation of the brain.

Rainey-Smith et al. reported that AQP4 should be considered when analyzing the effect of sleep on the glymphatic system and that it is a factor regulating glymphatic system activity during sleep (Shokri-Kojori et al. 2018). The perivascular polarization of AQP4 is highest during the rest period, and the loss of AQP4 eliminates the diurnal difference in glymphatic flow and drainage to the lymph nodes. A correlation between sleep deprivation and elevated Aβ levels has also been observed (Shokri-Kojori et al. 2018; Nedergaard and Goldman 2020). The above findings show that both a moderate amount of sleep and good quality of sleep help increase glymphatic activity, thus cleansing the brain. Even a small loss during sleep can affect its activity and lead to the accumulation of unwanted metabolites or beta-amyloid. Cleansing is most effective during the third and fourth stages of NREM, when the brain is characterized by delta waves. Glymphatic activity is significantly associated with the time to fall asleep or wake up. Therefore, the possibility of optimizing the lymphatic system through sleep regulation has exciting potential in the field of pharmacology.

Anesthesia

The most serious adverse effects of anesthetic drugs are the suppression of the respiratory, circulatory and thermoregulatory systems. In theory, any anesthetic drug that can cause these physiological changes can affect the function of the glymphatic/lymphatic system (Lindhardt et al. 2024). However, in recent years, the effects of different narcotic drugs on the glymphatic/lymphatic system have been controversial. Isoflurane, a narcotic drug, is widely used in preclinical research and clinical settings. Prolonged isoflurane exposure has been shown to be potentially neurotoxic. A recent study showed that AQP4 depolarization after long-term isoflurane anesthesia impaired the clearance of interstitial solutes in the glymphatic pathway, resulting in severe impairments of glymphatic efflux and influx (Dong et al. 2024). Researchers have also reported a relationship between glymphatic activity and the circulatory system. A strong negative correlation between heart rate and glymphatic influx has been observed under anesthesia. No correlation between the respiratory rate or systolic blood pressure and CSF flow was identified. Recent data have shown that sevoflurane impairs macroscopic CSF flow via the disruption of coherent global gray matter activity, indicating impaired glymphatic system function during sevoflurane anesthesia, which is likely mediated by the impairment of neuronal coherence (Zimmermann et al. 2025). Dexmedetomidine is a selective α2 adrenergic receptor agonist that hyperpolarizes neurons in the locus coeruleus and reduces the release of norepinephrine, thereby exerting hypnotic effects (Persson et al. 2022). The results of Benveniste's study revealed that, compared with isoflurane alone, dexmedetomidine combined with low-dose isoflurane increased the CSF volume by 2% in rats and the glymphatic system transport efficiency by 32%, which may be related to the inhibitory effect of dexmedetomidine on the function of the norepinephrine system in the coeruleus (Benveniste et al. 2017). Studies have shown that inhibiting the activity of the norepinephrine system in the locus coeruleus can improve glymphatic system function (Xie et al. 2013). Previous studies have shown that dexmedetomidine promotes the distribution of intrathecally injected drugs in the brain by accelerating the circulation of the glymphatic system (Lilius et al. 2019), suggesting that anesthetic drugs can promote the delivery of drugs targeting the brain by enhancing the function of the glymphatic system, providing new ideas for the clinical treatment of nervous system diseases (Persson et al. 2022). On the other hand, general anesthesia and sleep–wake states share many neurophysiological similarities, as both involve reversible changes in consciousness and the regulation of brain activity (Luo et al. 2025). One study revealed that, in anesthetized mice, increased lymphatic flow was associated with increased EEG delta power and a decreased heart rate. Therefore, in preclinical rodent studies, the correct selection of an anesthetic that increases delta power and reduces heart rate is necessary to optimize glymphatic function (Hablitz et al. 2019). Overall, the effect of anesthesia on the glymphatic/lymphatic system is a "double-edged sword" that may either enhance waste removal by simulating sleep or worsen nerve damage due to hemodynamic disturbances. In the future, multimodal monitoring, targeted molecular intervention and individualized anesthesia management should be combined to protect the function of the brain “scavenger” system to the greatest extent possible.

Body position

Interestingly, body position also affects the function of the glymphatic/lymphatic system. Dynamic contrast-enhanced magnetic resonance imaging (MRI) and dynamic simulation revealed that the glymphatic/lymphatic system transport efficiency was greater in the lateral position than in the supine and prone positions. Tracers in the brains of prone rats enter the glymphatic/lymphatic system and are slowly cleared, whereas transport and Aβ clearance in the glymphatic/lymphatic system are faster in the lateral and supine positions (Lee et al. 2015; Muccio et al. 2021). The possible reason is that the change in position affects the functions of the respiratory system and cardiovascular system, which in turn affects the pulsation that leads to the CSF/ISF cycle (Muccio et al. 2021). However, this mechanism needs to be further explored. These results suggest that lying on the side during sleep or anesthesia can promote the removal of brain metabolic waste, and future experimental designs concerning the glymphatic/lymphatic system should also pay attention to the positioning of experimental animals. However, at present, no direct evidence from human studies supports improvements in glymphatic/lymphatic system function, but this interference factor cannot be ignored, suggesting that we should pay attention to the interference of body postural factors when various imaging techniques are used to evaluate glymphatic/lymphatic system function to standardize the results. Do sleep, postural changes, or intracranial pressure fluctuations synchronously regulate the function of the glymphatic system?

Evidence of the involvement of the glymphatic/lymphatic system in cognitive impairment

In fact, a growing number of studies in recent years have documented a potential link between glymphatic/lymphatic function and cognitive impairment (Formolo et al. 2023; Gao et al. 2023; Xiong et al. 2024). Dysfunction of glymphatic/lymphatic clearance has been found in both VCI caused by stroke and cognitive impairment caused by neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) (Tian et al. 2022, 2023; Natale et al. 2021; Szlufik et al. 2024; Benveniste and Nedergaard 2022; Tang et al. 2022; Wang et al. 2023a; Zhong et al. 2023). The glymphatic/lymphatic system is increasingly viewed as a common final pathway in cognitive impairment and may help explain the crosstalk between vascular pathology and neurodegeneration (Nedergaard and Goldman 2020). Therefore, glymphatic/lymphatic transport dysfunction is involved in the pathophysiological mechanism of cognitive impairment and is a potential therapeutic target.

Alzheimer's disease

Over the past decade, an increasing number of studies have revealed the relationship between AD and glymphatic/lymphatic dysfunction (Ciurea et al. 2023; Nedergaard and Goldman 2020; Guo et al. 2023; Yamada and Iwatsubo 2024; Huang et al. 2024). Notably, PVS enlargement around the basal ganglia is associated with reduced cognitive abilities in terms of language, attention, and executive function in patients with AD, suggesting that these cognitive areas are more susceptible to glymphatic damage (Zhang et al. 2024a). The main pathological features of AD are the accumulation of Aβ plaques and neurofibrillary tangles of the hyperphosphorylated protein tau. Although 75% of Aβ excretion is dependent on blood–brain barrier transport, recent studies have shown that glymphatic/lymphatic flow plays a crucial role in AD (Iliff et al. 2012; Gao et al. 2023). One hour after injecting fluorescently labeled Aβ into the brain parenchyma, the amount of Aβ remaining in the brain tissue of mice with damaged meningeal lymphatic vessels was twice that of mice without damaged meningeal lymphatic vessels. Six weeks after the destruction of meningeal lymphatic vessels, the accumulation of Aβ in the hippocampus of transgenic AD mice increased exponentially, and their cognitive function further declined. In a mouse model of AD, VEGF-C overexpression induced meningeal lymphatic vessel gushing and slowed cognitive decline (Louveau et al. 2015; Mesquita et al. 2018). Conversely, in the same model of AD, both ultraviolet ablation of meningeal lymphatic vessels and mechanical ligation of cervical lymphatic vessels exacerbated amyloid plaque formation and the deterioration of cognitive function. In the early stages of AD, a decrease in glymphatic/lymphatic system transport occurs before Aβ deposition (Huang et al. 2024; Peng et al. 2016). Therefore, the regulation of glymphatic/lymphatic system function is expected to become a therapeutic target for AD, providing new hope for the treatment of AD patients (Cheng et al. 2020; Chachaj et al. 2023; Xu et al. 2023).

Another important pathological change in AD is the abnormal accumulation of hyperphosphorylated tau protein, which together with Aβ plaques in the brain, leads to neurodegeneration, and correct clearance of hyperphosphorylated tau protein helps prevent the development of AD. Recent animal studies have confirmed that the loss of function of the cerebral glymphatic/lymphatic system delays tau clearance and aggravates tau pathology (Harrison et al. 2020). The tau pathology of AQP4 knockout mice was more severe than that of control mice, suggesting that the glymphatic/lymphatic system mediated by the AQP4 protein plays an important role in tau clearance (Ishida et al. 2022). Patel et al. injected near-infrared absorption dye combined with the tau protein into the rat brain parenchyma for 48 h and 72 h to further investigate the role of dural lymphatic vessels in tau protein clearance and observed that the residual amount of tau protein in the brains of animals with meningeal lymphatic vessel functional defects was twice that of animals in the control group through fluorescence molecular tomography and fluorescence quantitative detection. Similar results were observed after tau protein residues were detected in plasma 48 h later (Patel et al. 2019). This study suggests that in the absence of dural lymphatic function, extracellular tau protein cannot be effectively cleared from the central nervous system to the periphery. The above two studies confirmed that the glymphatic system and meningeal lymphatic vessels cooperate to ultimately complete the clearance of tau protein, thus delaying the occurrence and development of AD.

Key molecules involved in AD, i.e., Aβ and tau, are increasingly recognized to be excreted by the glymphatic system and then cleared by the meningeal lymphatic vessels. Moreover, the risk factors and pathogenesis of AD are closely related to impaired glymphatic/lymphatic function (Yamada and Iwatsubo 2024). However, whether decreased glymphatic/lymphatic system function is a "cause" or "effect" of AD needs further exploration. Perhaps Aβ clearance disorders may be both pathological products and drivers of impaired glymphatic/lymphatic function. How meningeal lymphatic vessels collaborate with the glymphatic system to clear abnormal proteins in AD patients remains unclear, and more research is needed. Most current treatments for AD mainly target Aβ and tau directly. A crucial challenge is to determine whether enhancing the glymphatic/lymphatic clearance pathway in the brain is also a potential therapeutic strategy. Finally, from the standpoint of diagnostic biomarkers for AD, the lymphatic/meningeal lymphatic system may also be valuable.

Vascular cognitive impairment

Vascular cognitive impairment (VCI) is a clinical syndrome that ranges in severity from mild cognitive impairment to dementia and is secondary to cerebrovascular disease. Previous studies of VCI have focused on neuroinflammation, blood–brain barrier disruption, or neurovascular unit dysfunction. Recent studies revealed that the dysfunction of metabolic waste clearance pathways is also involved in the pathogenesis of VCI (Gouveia-Freitas and Bastos-Leite 2021; Tang et al. 2022; Ueno et al. 2019; Cao et al. 2022; Li et al. 2022b; Ke et al. 2022). Impairment of the lymphatic system has been shown to be associated with cerebrovascular risk factors such as hypertension, diabetes, and lipid metabolism. Since these disorders are closely associated with VCI, the findings also support the potential role of lymphatic dysfunction in the development of VCI (Tian et al. 2022). Tang et al. conducted a study of 133 patients with CSVD who underwent neuropsychological testing and MRI. After adjusting for six common risk factors (age, education, high blood pressure, diabetes, smoking and alcohol abuse) as well as markers of cardiovascular disease, the ALPS index was found to correlate independently and linearly with overall cognitive function, executive function, attention function and memory (Tang et al. 2022). These findings suggest that damage to the glymphatic system is independently associated with cognitive impairment in CSVD patients. A cross-sectional study revealed that the severity of PVS enlargement, such as PVS enlargement around the basal ganglia, was associated with early acute ischemic stroke with cognitive impairment, which can help in the early diagnosis and evaluation of patients with early acute ischemic stroke presenting with cognitive impairment (Tu et al. 2024).

Chronic cerebral hypoperfusion can lead to cerebral vascular metabolic disorders and glymphatic/lymphatic system function impairments, which eventually manifests as white matter injury and cognitive dysfunction (Cao et al. 2022). The impaired drainage of meningeal lymphatic vessels and lymphatic pathways is specifically related to the pathogenesis of white matter hyperintensity (WMH), and enhancing meningeal lymphatic function is a promising therapeutic strategy that can delay or even prevent the growth of WMH (Zhou et al. 2024a). Studies have shown that different mechanisms exist for the formation of periventricular WMH and deep WMH. Periventricular WMH is attributed mainly to venous injury caused by the dysfunction of the glymphatic/lymphatic pathway, whereas deep WMH may be affected by both hypoperfusion and dysfunction of the glymphatic/lymphatic clearance pathway (Cai et al. 2022). A large prospective multicenter study revealed an association independent of potential confounders between periventricular WMH and elevated amyloid levels in the brain, suggesting that WMH is associated with impaired amyloid clearance in the brain parenchyma and eventual dementia (Straaten et al. 2008). In mice with chronic cerebral hypoperfusion, significant white matter damage was associated with cognitive impairment, accompanied by impaired glymphatic system function. A previous study also showed that glymphatic dysfunction was associated with changes in brain perfusion and the loss of AQP4 polarization (Cao et al. 2022). These findings provide new insights into the relationships among hemodynamics, glymphatic transport, white matter damage, and cognitive changes after chronic cerebral hypoperfusion.

Moyamoya disease (MMD) is a cerebrovascular disease characterized by chronic progressive stenosis or occlusion at the end of the internal carotid artery, the beginning of the anterior cerebral artery and the middle cerebral artery of unknown etiology, as well as secondary abnormal vascular network formation at the cerebral base. MMD is often accompanied by cognitive dysfunction. Cognitive decline in patients with MMD is closely related to structural damage to the brain (Zhu et al. 2024a). Both white matter damage and gray matter damage are common in MMD patients and are closely related to cognitive impairment, in which white matter damage plays a particularly important role (Kazumata et al. 2015). A close relationship exists between glymphatic system dysfunction and white matter structural damage in MMD patients, and, in particular, periventricular WMH plays a role in glymphatic system-related cognitive impairments (Zhu et al. 2024a). Hara et al. studied the relationship between cerebral hemodynamics and glymphatic function in patients with MMD. They reported that a decrease in the ALPS index was associated with an increased interstitial free water content, reduced cerebral blood flow, and executive dysfunction (Hara et al. 2024). These findings suggest that chronic hemodynamic disturbances in MMD patients may impair glymphatic function and lead to cognitive decline. Similarly, Zeng et al. reported that lymphocyte damage in MMD patients is associated with cognitive dysfunction (Zeng et al. 2024). However, the exact role of the glymphatic system in the progression of cognitive impairment in patients with MMD remains to be further explored.

Large vessel disease and carotid artery stenosis are the key pathogeneses of VCI (Li et al. 2022b). Hemodynamic pulsation is the main driving factor of glymphatic/lymphatic transport (Mestre et al. 2018). In mice, lymph effusion and lymph inflow are severely impaired on Day 3 after bilateral common carotid artery stenosis and gradually recover spontaneously over the following weeks (Cao et al. 2022). Studies have shown that bilateral common carotid artery stenosis also causes cognitive impairment through the progressive worsening of neurovascular unit dysfunction and Aβ protein accumulation. In summary, investigating the role of the glymphatic system and the lymphatic system in VCI is an important research direction in the field of neuroscience. These two systems are closely related to the pathological mechanism of VCI by clearing metabolic waste and maintaining brain homeostasis and may provide targets for future diagnosis and treatment.

Parkinson's disease-related cognitive impairment

PD is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of misfolded α-synuclein in the endoplasmic bodies. Extracellular amyloid and tau protein accumulation have also been found in patients with PD-related dementia and mild cognitive impairment, which are the same pathological features as AD (Robinson et al. 2018; Petrou et al. 2015). In addition, Aβ may even contribute to cognitive decline in PD patients, especially in those with lower CSF Aβ42 levels, which is associated with a faster rate of cognitive decline, poorer executive function performance, and delayed recall (Alves et al. 2014; Bäckström et al. 2015; Stav et al. 2015). Thus, the pathology of AD (Aβ and tau) may have a synergistic effect with α-synuclein pathology, resulting in a worse prognosis.

The pathophysiological changes underlying the cognitive decline in patients with PD are unclear, and one potential mechanism may be reduced clearance of metabolic waste and protein aggregates in the brain parenchyma due to dysfunction of the glymphatic/lymphatic system (Ding et al. 2017; Debette et al. 2019; Chen et al. 2021; Buccellato et al. 2022; Gui et al. 2024; Yue et al. 2024; Ren et al. 2025). α-Synuclein deposition in the brains of PD patients is negatively correlated with AQP4 expression, suggesting that glymphatic/lymphatic dysfunction is related to protein accumulation and plays a role in the progression of PD (Hoshi et al. 2017). After deep cervical lymph node ligation blocked meningeal lymphatic drainage in A53T mice (PD model), the lymphatic inflow of CSF tracers in the mouse brain was reduced, resulting in α-synuclein accumulation, glial cell activation, inflammation, a reduction in the number of dopaminergic neurons, and movement disorders (Zou et al. 2019). PVSs are found in both white matter and gray matter, including in the basal ganglia. PVS enlargement, which has been quantified via MRI in several studies as either a larger PVS volume or a greater incidence of dilated PVSs, is thought to indicate glymphatic system dysfunction (Chen et al. 2022; Donahue et al. 2021; Ramirez et al. 2022). Studies have shown that PD patients with enlarged basal ganglia PVSs have lower CSF Aβ42 baseline levels and MoCA scores (Park et al. 2019; Donahue et al. 2024). Recent studies have shown that a high baseline PVS volume in the basal ganglia is associated with declines in attention, executive function, and global cognition in patients with PD (Foreman et al. 2024). Studies have shown that PVS enlargement in the temporal lobe is also associated with neuropsychiatric symptoms in patients with PD, suggesting that PVS enlargement in the basal ganglia may be a valuable early indicator of cognitive decline in PD patients (Kim et al. 2024; Luo et al. 2024). A recent study revealed that PVS enlargement in PD patients is also associated with low-frequency EEG slow-wave activity, motor symptoms, and REM sleep behavior disorders, providing new insights into the pathogenesis of PD (Meinhold et al. 2025). These studies provide a new theoretical basis for the relationship between glymphatic/lymphatic transport and cognitive changes after PD as well as a new strategy for the treatment of PD.

Idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is an abnormal CSF circulation disorder characterized by an elevated nonintracranial pressure and is accompanied by a typical triad of symptoms, namely abnormal gait, urinary incontinence, and cognitive impairment. The pathophysiological mechanism of iNPH has not been fully elucidated. Recently, the role of the glymphatic/lymphatic system in the pathogenesis of iNPH has attracted increasing attention (Bae et al. 2021; Tan et al. 2021; Soldozy et al. 2022; Colman et al. 2024). Ringstad and Eide were the first to present data on glymphatic/lymphatic dysfunction in human iNPH patients (Ringstad et al. 2017, 2018; Eide and Ringstad 2019). They compared the efficiency of glymphatic/lymphatic clearance in iNPH patients with that in normal controls by injecting contrast agents. The results revealed that the clearance rate of the glymphatic/lymphatic system in iNPH patients was significantly reduced, suggesting that disorders of the glymphatic/lymphatic system may be one of the mechanisms leading to this disease. In addition, studies have shown that the expression of AQP4 in the astrocytes of iNPH patients is reduced, which interferes with the homeostasis of the glymphatic/lymphatic system in the brain (Eide and Hansson 2018; Hasan-Olive et al. 2019). Taken together, these findings suggest that the glymphatic/lymphatic system is involved in the pathogenesis of iNPH and may be a potential therapeutic target.

Aging-related cognitive impairment

The above findings suggest that glymphatic/lymphatic dysfunction is associated with cognitive decline in patients with a variety of neurodegenerative diseases, including AD, PD and iNPH (Verghese et al. 2022). Some scholars have emphasized that glymphatic/lymphatic failure may be a common pathway through which all neurodegenerative diseases eventually lead to dementia (Nedergaard and Goldman 2020). Recent research suggests that water and metabolites are rapidly and efficiently cleared through multiple lymphatic drainage pathways, with the clearance ability decreasing with age (Love and Miners 2016; Knopman et al. 2016). The glymphatic/lymphatic system plays a protective role in normal age-related cognitive decline (Zhang et al. 2019; Chen et al. 2024). Data have shown that glymphatic/lymphatic dysfunction accounts for 21.3% of normal age-related cognitive decline (Wang et al. 2023b). A DCE-MRI study revealed that both the glymphatic system and meningeal lymphatic vessels may be damaged in the aging human brain (Zhou et al. 2020). Glymphatic/lymphatic function decreases with age as arteries in the brain stiffen and pulse amplitude decreases (Zhang et al. 2019). Because AQP4 is misaligned during astrocyte formation, aging can also lead to glymphatic dysfunction (Li et al. 2022c). In addition to the cerebrovascular system, the efficacy of glymphatic fluid transport is directly related to sleep quality. Sleep disorders are common in elderly individuals. Disturbances in their sleep structure may lead to dysfunction of the glymphatic/lymphatic system, greatly reducing the clearance of CSF and the excretion of metabolites.

Therefore, we believe that glymphatic/lymphatic system dysfunction affects the clearance of metabolic waste from the brain by CSF, leading to the accumulation of metabolic waste in the brain and accelerating the aging process and its associated cognitive impairment (Xiong et al. 2024). Disruption of the sleep–wake cycle can also lead to dysfunction of the glymphatic/lymphatic system, further accelerating the body's aging process (Mattis and Sehgal 2016).

Perioperative neurocognitive disorder

Perioperative neurocognitive disorder (PND) is a common complication of the nervous system after anesthesia and is characterized mainly by declines in memory and cognitive ability. Cognitive decline occurs in approximately 25% of older patients who undergo surgery, and permanent cognitive impairment occurs in 50% of older patients (Xiang et al. 2019). Dysfunction of the glymphatic/lymphatic system after surgery may be one of the causes of PND (Roy et al. 2024). Significant accumulation of Aβ and tau proteins was detected in the brain parenchyma after anesthesia and surgery, similar to the pathological changes in AD (Terrando et al. 2011; Evered et al. 2016; Gerlach and Chaney 2018; Zhu et al. 2024b).

Under normal physiological conditions, the mechanisms regulating cerebral glymphatic/lymphatic function include arterial pulsation and breathing. The heart rate, blood pressure and arterial pulsation clearly change during anesthesia, and spontaneous negative-pressure breathing changes to positive-pressure ventilation. Under general anesthesia, the arousal mechanism is also significantly inhibited (Schiff 2020). Anesthesia-induced pathological changes, such as glymphatic CSF-ISF exchange disorders, are associated with the occurrence and progression of the disease (Dong et al. 2024). Therefore, PND may be associated with the glymphatic/lymphatic dysfunction caused by anesthesia (Ren et al. 2021). Clearance by the glymphatic/lymphatic system is closely related to sleep, and sleeping better facilitates the clearance of metabolites. However, due to the interference of many factors such as postoperative pain, the environment and stress, sleep disorders often occur in the perioperative period (Whitlock et al. 2017; Su and Wang 2018). Postoperative sleep disorders are characterized by reduced durations of slow wave and REM sleep. In particular, REM sleep disorders may have significant negative effects on PND (Lazic et al. 2017). Recent studies in elderly mice have shown that laparotomy disrupts the polarization of AQP4 and induces glymphatic/lymphatic dysfunction and PND. However, restoring the polarization of AQP4 can enhance the glymphatic/lymphatic clearance of neurotoxic molecules and alleviate PND (Zhu et al. 2024c). Studies have also revealed that long-term application of isoflurane for anesthesia can lead to glymphatic/lymphatic system dysfunction by inducing AQP4 depolarization. Therefore, improving AQP4 polarization can alleviate glymphatic/lymphatic system dysfunction and may be a treatment option for PND (Dong et al. 2024). The data also revealed that surgical activation of the HMGB1/TLR4/NF-κB pathway aggravated glymphatic/lymphatic dysfunction and neuroinflammation, eventually leading to cognitive impairment in middle-aged mice with preoperative cerebral lymphatic drainage injury (Zhu et al. 2024b). In summary, the above factors are involved in perioperative glymphatic/lymphatic dysfunction, which together lead to the occurrence of cognitive impairment. In conclusion, cerebral glymphatic/lymphatic drainage disorders may be one of the potential mechanisms related to the occurrence of PND, and restoring PND function may be a potential strategy for the treatment of PND.

Neuroimaging technology

Neuroimaging techniques have been used to visualize and quantify glymphatic/lymphatic flow in the body, providing unprecedented insights into glymphatic/lymphatic system function and opening new avenues for the diagnosis and treatment of many diseases (He et al. 2023). Positron emission tomography (PET) and MRI are currently the most commonly used imaging techniques to study the glymphatic/lymphatic system (Steward et al. 2021; Park et al. 2023; Hsu et al. 2023; Okazawa et al. 2024; Prasuhn et al. 2024).

In recent years, PVS enlargement has been associated with a variety of neurological disorders, such as AD and cerebral small vascular disease, and thus studying methods for evaluating PVS enlargement and its relationship with these diseases is very important (Tu et al. 2024). Traditionally, PVS evaluation has mainly relied on MRI, especially T2-weighted imaging, but a manual evaluation is subjective and inefficient (Wardlaw et al. 2020). Most scores provide a qualitative estimate of the extent of the PVS based on the approximate volume of the PVS in an anatomically defined area. The PVS can be quantified using visual scoring or computational methods (Agarwal et al. 2024). Thus, in a defined brain scan slice, the presence of fewer than 10, 11–20, 21–40, and more than 40 perivascular spaces within the basal ganglia will produce scores of 1, 2, 3, and 4, respectively, and midbrain PVSs are rated 0 (none visible) or 1 (visible) (Wardlaw et al. 2020; Taoka et al. 2024; Potter et al. 2015). The latter enables the assessment of the PVS number, total and individual PVS volumes, and PVS width, length, clustering, and orientation (Agarwal et al. 2024). However, this qualitative score is relatively insensitive and is limited by lower and upper boundary effects. To date, no equivalent methods have been developed to quantify the space around blood vessels in human tissue slices. Visualization and quantification of the glymphatic/lymphatic system in the body can provide an early diagnosis associated with glymphatic/lymphatic dysfunction. An early diagnosis is essential for the effective management of these diseases, as it allows the timely initiation of treatments to improve the disease prognosis. In addition, neuroimaging may provide a means to measure the effectiveness of treatments to improve glymphatic/lymphatic function. With in vivo dynamic imaging technology, simultaneous capture of the real-time interaction between the lymphatic system and meningeal lymphatic vessels (such as the transport path of CSF from the lymphatic system to the meningeal lymphatic system) is difficult.

As mentioned above, in patients with AD and other neurological disorders, PVS dilation observed on MRI can be considered a biomarker of glymphatic/lymphatic dysfunction and amyloid accumulation (Hsu et al. 2023; Taoka and Naganawa 2020; Perosa et al. 2022; Kamagata et al. 2022). MRI examination via the intrathecal injection of gadolinium-based contrast agents has been used to observe the glymphatic/lymphatic system in humans. However, gadolinium-based contrast agents can cause serious neurotoxicity (Lei et al. 2017; Benveniste et al. 2021). A new indicator for estimating the activity of the lymphatic system has been developed using diffusion tensor image (DTI) analysis of signals along the perivascular space (ALPS) (Taoka et al. 2017, 2022). The ALPS index can be used to assess the glymphatic/lymphatic system without the help of contrast agents. The principle is that the minimum perivascular water diffusion corresponds to an index close to 1, which increases as the perivascular diffusion rate increases. Recently, researchers compared this approach to the classical enhanced lymphatic MRI method involving the intrathecal injection of gadolinium and demonstrated that the ALPS index reflects glymphatic/lymphatic clearance function (Zhang et al. 2021). Huang et al. suggested that glymphatic/lymphatic damage, as indicated by the ALPS index, may precede significant Aβ deposition and predict the clinical progression of amyloid deposition, neurodegeneration, and AD (Huang et al. 2024). Recent studies have shown that the ALPS index can predict amyloid deposition, brain atrophy, clinical progression, and cognitive decline in AD patients (Huang et al. 2024). A study using DTI-ALPS technology revealed that glymphatic/lymphatic activity in patients with cognitive impairment was significantly decreased and positively correlated with MMSE and MOCA scores (Zhong et al. 2023; Steward et al. 2021; Taoka et al. 2017; Ma et al. 2021; Liang et al. 2023). A decrease in the DTI-ALPS index indicates damage to the glymphatic/lymphatic system in patients with cognitive impairment. The evidence highlights the importance of DTI-ALPS in detecting functional changes in the glymphatic/lymphatic system and highlights the potential value of the ALPS index as a biological indicator of the neuropathological state (Zhong et al. 2023; Ke et al. 2022; Costa et al. 2024; Shang et al. 2024; Jungwon et al. 2025). However, it is also susceptible to a variety of physiological factors. For example, changes in axonal tissue that occur with aging and neurodegeneration can lead to a decrease in the ALPS index, suggesting that the decline in the ALPS index observed in patients with neurodegenerative diseases may also be influenced by disease-related changes in the properties of white matter tracts (Wright et al. 2024). In addition, DTI has several technical limitations, such as an insufficient resolution to distinguish between tiny PVSs and other structures and nonuniform ROI placement (Taoka et al. 2024). The ALPS index focuses only on the paraventricular region and may not fully reflect the functional status of the glymphatic system of the whole brain. In addition, DTI has limited spatial resolution (usually 2–3 mm), while the diameter of the PVS is usually less than 1 mm. This limited resolution can result in a partial volume effect, reducing the specificity of the measurement. Moreover, the function of the glymphatic/lymphatic system is circadian and dependent on posture. Conventional MRI is usually performed in a single scan while the patient is resting and awake and may not capture its dynamic changes. Studies verifying the direct association between the ALPS index and the dynamic activity of the glymphatic/lymphatic system, such as the rate of CSF-ISF exchange, are lacking. Therefore, the DTI-ALPS index should be considered as an auxiliary research tool at present and should be interpreted in combination with the clinical context and other biomarkers to avoid an over-inference of its independent diagnostic value (Taoka et al. 2024).

Most studies of meningeal lymphatic vessel imaging have been limited to animal studies. Reliable methods for clearly viewing the meningeal lymphatic vessels in humans are still lacking. At present, MRI-based meningeal lymphatic vessel imaging is still in the exploratory stage. Recent studies have used enhanced MRI to visualize the meningeal lymphatic vessels of the brain (Absinta et al. 2017; Ringstad and Eide 2020; Jacob et al. 2022). Following an intravenous injection, contrast agent molecules are delivered from blood vessels to the meningeal lymphatics. Subsequent, black blood imaging suppresses blood signals while clearly highlighting lymphatic signals (Fang et al. 2025). Fluid-attenuated inversion recovery (FLAIR) imaging is one of the most commonly used techniques in routine clinical MRI and can also be used to visualize cerebral lymphatic structures. Three-dimensional-T2-FLAIR sequences have high resolution, reduce the effect of artifacts, and are more conducive to displaying the structure of smaller meningeal lymphatic vessels, which encourages the further development of these approaches for diagnostic and therapeutic applications in CNS diseases (Fang et al. 2025). Advances in MRI technology, such as 7-T ultrahigh field intensity MRI and AI-assisted image segmentation, are expected to overcome the current resolution limitations. In addition, multimodal image fusion methods (such as PET-MRI combined with lymphatic-targeting tracers) may provide a new strategy for the dynamic monitoring of the meningeal lymphatic system in vivo.

PET research and the use of neuroimaging have also revealed information about the physiological function of the glymphatic/lymphatic system and its role in related diseases. PET scans using [11C]-PiB, a tracer that is sensitive to Aβ and is thought to also be sensitive to changes in CSF clearance in AD patients, have revealed deficiencies in CSF clearance in AD patients (Okazawa et al. 2024; Schubert et al. 2019). Using PET, Li and collaborators recently identified a relationship between brain Aβ deposition and impaired clearance in patients with sporadic AD (Li et al. 2022c).

The glymphatic system may be related to sleep-dependent global brain activity, as recently observed with resting-state functional magnetic resonance imaging (rsfMRI) (Liu et al. 2017b, 2018). Global blood oxygen level-dependent (gBOLD) resting-state functional MRI (rs-fMRI) signals of < 0.1 Hz have been associated with cerebrospinal fluid (CSF) dynamics. Therefore, low-frequency oscillations in the CSF are a possible resource for noninvasively quantifying glymphatic system dynamics (Han et al. 2021, 2023a, 2023b, 2021, 2024). Recently, gBOLD and CSF coupling was applied as an index to reflect glymphatic function (Liu 2024; Zhao et al. 2025). Studies have confirmed that this gBOLD–CSF coupling exists either during sleep (Fultz et al. 2019) or wakefulness (Yang et al. 2022) and has a much greater effect on CSF inflow than on cardiac pulsation during wakefulness (Yang et al. 2022). Through resting-state functional MRI, quantifying the gBOLD–CSF coupling strength as the cross-correlation between baseline gBOLD and CSF inflow signals can be used to evaluate glymphatic function and its association with the clinical manifestations of diseases associated with cognitive impairment, such as PD, AD and behavioral variant frontotemporal dementia (Han et al. 2021; Han et al. 2021; Jiang et al. 2023; Wang et al. 2023c). Recent results suggest that gBOLD–CSF coupling may be a sensitive index metric for evaluating glymphatic dysfunction before PD treatment (Wang et al. 2023c).

In summary, although many matters are still being debated concerning the glymphatic/lymphatic system, such as the flow mode of CSF in the brain parenchyma, the driving force of the glymphatic system, and the outflow mode of CSF after completing exchange with the ISF, the common consensus is that CSF can enter the brain parenchyma to exchange substances with the ISF and clear brain metabolites. From this point of view, future research needs to further improve noninvasive or minimally invasive methods to study the glymphatic/lymphatic system and accurately capture glymphatic/lymphatic system changes, which will help us deepen our understanding of the pathological mechanisms of various neurological diseases and thus improve prevention and treatment strategies for these diseases.

Therapeutic targets of the glymphatic/lymphatic system for cognitive impairment

As mentioned above, the glymphatic/lymphatic system is involved in the pathogenesis of many neurological diseases (Huang et al. 2024; Beschorner and Nedergaard 2024; Zhang et al. 2024b; Zhou et al. 2024b; Salvador et al. 2024; Sun et al. 2025). Therefore, researchers hope that it will become a pharmacological target for the treatment of neurological diseases. Next, we discuss several potential therapeutic targets of the glymphatic/lymphatic system for the treatment of cognitive impairment.

Modulation of sleep

Slow-wave activity on an electroencephalogram (EEG) is consistent with deep NREM, which is the optimal stage for glymphatic flow to remove metabolic waste (Gao et al. 2023). Previous research has shown that glymphatic/lymphatic flow in EEG recordings is positively correlated with cortical delta power and that beta power is negatively correlated with heart rate (Hablitz et al. 2019). A previous study revealed that slowly oscillating neural activity precedes the coupled waves of blood and CSF flow in the brain (Fultz et al. 2019). During natural sleep, the interstitial space increases by 60%, resulting in a significant increase in the convectional exchange of CSF with ISF and Aβ clearance (Xie et al. 2013). Therefore, we believe that adjusting the sleep structure may be a new way to treat AD.

Modulation of AQP4

As one of the most important components of the glymphatic system, AQP4 is a valuable target for the future treatment of cognitive impairment. Enhancing the function and efficiency of the glymphatic system helps delay or prevent the accumulation of abnormal proteins in the brain, which is crucial in clearing tau protein from the circulation. Preliminary preclinical studies in which mouse models were pretreated with a novel AQP4 accelerator, TGN-073, revealed that the turnover rate of labeled water in the PVS increased in TGN-073 treated mice (Huber et al. 2018). The novel AQP4 inhibitor, TGN-020 significantly impaired glymphatic CSF-ISF exchange and accelerated tau protein deposition (Harrison et al. 2020). These findings suggest that AQP4 not only plays an important role in the lymphatic system but also holds promise as a new target for the treatment of AD and other neurodegenerative diseases. Recently, some scholars have suggested that 40 Hz light flickering can increase lymphatic flow in awake mice by increasing AQP4 polarization and vasomotor activity, thereby increasing lymphatic flow, suggesting that 40 Hz light flickering has potential as a new noninvasive strategy to increase lymphatic flow and has translational potential for treating neurological diseases (Sun et al. 2024).

Although AQP4 is a potential therapeutic target for neurological disorders, many questions remain. For example, AQP4 is expressed not only in the central nervous system but also in other parts of the body, such as the muscle membrane, renal intramedullary duct, gastric parietal cells, and exocrine glandular epithelium. Therefore, targeting AQP4 in astrocytes in important to consider for therapy to avoid peripheral AQP4 binding and prevent side effects (Verkman et al. 2017). In addition, AQP4 has two major isomers that form two different tetramers (Verkman et al. 2017). Therefore, the specificity of drugs for different tetramers is also a problem that needs to be considered.

Modulation of CSF flow in the PVS

The PVS is not only a key channel for the exchange of CSF and cerebral interstitial fluid but also a core structure of the glymphatic system that clears metabolic waste products (such as β-amyloid protein and tau protein). Its abnormal function is closely related to cognitive disorders such as AD and VCI. CSF flow in the PVS is influenced by many factors, among which arterial fluctuations are the main driving force of CSF flow in the PVS. Abnormal hemodynamics can weaken arterial pulsation and reduce glymphatic clearance efficiency. Decreased cerebral blood flow has been identified as an early sign of several neurodegenerative diseases and is often observed in patients with heart failure. While brain autoregulation can usually compensate for reduced cardiac output by reducing cerebrovascular resistance, this process does not occur during heart failure. One study revealed that at 6 and 12 weeks after myocardial infarction, increased glymphatic influx was proportional to the decreased EF. Despite increased influx, glymphatic clearance was not proportionally affected 12 weeks after myocardial infarction, indicating a glymphatic system disorder (Kritsilis et al. 2024). Dobutamine, an adrenergic agonist, has been shown to increase the rate of perivascular CF-ISF exchange by increasing arterial pulsation and cardiac contractility (Iliff et al. 2013). This finding also explains how heart failure reduces lymphatic blood flow exchange and accelerates cognitive decline. Therefore, the regulation of rhythm and cardiac circulation can promote glymphatic circulation and is promising as a new target for the treatment of neurological diseases.

On the other hand, the PVS is a pathway through which immune cells (such as macrophages) enter the brain parenchyma, and chronic inflammation may mediate neurodegenerative damage through the PVS. Recent research has shown that LYVE1 + perivascular macrophages modulate ECM remodeling in the PVS, thereby regulating arterial motion and CSF flow and regulating lymphatic flow by mediating the degradation of ECM proteins such as collagen IV and lamin (Drieu et al. 2022; Kaur et al. 2024). In summary, modulating CSF flow in the PVS from a hydrodynamic perspective could serve as a new basis for the treatment of cognitive impairment, the core goal of which would be to restore the homeostasis of the brain microenvironment and its ability to remove metabolic waste.

Regulation of the meningeal lymphatic vessels

Another treatment option has been suggested by researchers. In these studies, injecting VEGF-C into older mice safely increased the meningeal lymphatic vessel diameter and enhanced meningeal lymphatic drainage, improving cerebral perfusion and cognitive function (Louveau et al. 2015; Mesquita et al. 2018). In addition, the combined treatment of older mice with VEGF-C and Aβ immunotherapy cooperatively reinforced lymphatic function, cleared Aβ plaques, and improved cognitive function (Mesquita et al. 2021). These studies suggest the therapeutic potential of strategies targeting meningeal lymphatic vessels.

Surgical intervention

Cervical deep lymphatic-venous anastomosis is performed using ultra-microsurgical technology to rebuild the cerebral lymphatic circulation and promote the removal of metabolites from the brain, with the goal of improving the cognitive function and ameliorating the neurodegenerative symptoms of patients and achieving the clinical purpose of alleviating or even curing AD. This operation not only has a sufficient basis in theory but also has achieved remarkable results in practice, improving the prognosis of patients in emotional and cognitive aspects. This innovative treatment option provides a new strategy for the treatment of AD.

In conclusion, the glymphatic/lymphatic system is an important component of the brain, and its dysfunction has a complex relationship with the onset of cognitive impairment. Advanced neuroimaging techniques are helping to improve our understanding of this system. With neuroimaging, we can develop innovative therapies that target the glymphatic/lymphatic system and change the trajectory of cognitive impairment. The future holds promise for treating cognitive impairment by targeting the glymphatic/lymphatic system and ushering in a new era of personalized treatment.

Conclusion

In summary, our understanding of glymphatic/lymphatic function is only slightly more than ten years old, but its emergence has opened new directions for exploring the mechanisms of cognitive impairment. The development of an effective method to increase glymphatic/lymphatic circulation is a desirable goal for the treatment of cognitive impairment. This strategy has the potential to open a new chapter in the diagnosis and treatment of cognitive impairment. However, many controversial and unknown aspects of the glymphatic/lymphatic system remain, and more scholars are needed to conduct in-depth research in this field. Its complexity requires interdisciplinary collaboration (e.g., integration of fluid mechanics, immunology, and imaging). In the future, its role in disease must be clarified through more accurate technological methods and longitudinal research before the leap from a “mechanistic analysis” to “precise intervention” can finally be realized.

Author contributions

ZH designed and wrote the manuscript. JS contributed to the study conception, carried out the logic examination and participated in the review of professional medical content of the manuscript. The authors contributed to the article and approved the final version.

Funding

This work was supported by the Science and Technology Development Plan Project of Jilin Province in China (YDZJ202401696ZYTS).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

Ethical approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.