Glymphatic Dysfunction in Alzheimer’s Disease: Insights from Recent Research and Relevance to Clinical Practice
A comprehensive review published in Science in July 2025 by Keil et al. presents an updated appraisal of glymphatic system dysfunction in Alzheimer’s disease (AD). The paper synthesises more than a decade of experimental and clinical research, highlighting the glymphatic system’s role in clearing metabolic waste from the brain and its possible contribution to the development and progression of AD pathology.
At Alzheimer’s Clinics UK, where Transcranial Pulse Stimulation (TPS) is offered for patients with mild to moderate Alzheimer’s, this evolving understanding is relevant. TPS has known effects on cerebral perfusion and neural activity, which intersect with several of the physiological factors identified as important for glymphatic function. This article outlines the major findings of the Keil review and their potential implications for clinical strategies aimed at slowing disease progression.
The Glymphatic System: A Brain-Wide Clearance Mechanism
The glymphatic system is a recently characterised network for fluid exchange in the brain, involving the influx of cerebrospinal fluid (CSF) along periarterial spaces, its exchange with interstitial fluid (ISF), and the removal of solutes via perivenous drainage routes. It is supported by aquaporin-4 (AQP4) water channels located on astrocytic endfeet, and is regulated by physiological forces including arterial pulsation, vasomotion, and sleep-dependent changes in extracellular volume.
Rodent studies have demonstrated that the glymphatic system is most active during deep sleep, particularly during non-REM phases associated with high delta wave activity. During these periods, the extracellular space expands, promoting more efficient solute transport. In contrast, wakefulness and elevated central noradrenergic tone suppress glymphatic function. This system provides a route for the clearance of neurotoxic proteins such as amyloid beta (Aβ) and tau, both of which are centrally implicated in AD pathology.
Experimental Evidence of Glymphatic Dysfunction in AD
In transgenic mouse models of Alzheimer’s disease, impaired glymphatic clearance has been shown to accelerate the accumulation of both Aβ and tau. Deletion of the Aqp4 gene, mislocalisation of AQP4 away from perivascular endfeet, and sleep disruption each independently reduce glymphatic transport and worsen pathological burden.
Moreover, rodent models of several non-genetic AD risk factors—including ageing, hypertension, type 2 diabetes, cerebrovascular disease, and traumatic brain injury—show glymphatic impairment. These models often exhibit reduced CSF influx, loss of AQP4 polarity, and slower interstitial solute efflux. For example, ageing alone has been shown to impair glymphatic exchange, even in the absence of other comorbidities, and this impairment correlates with a reduction in perivascular AQP4 localisation.
These findings support the view that glymphatic dysfunction is not merely a consequence of AD pathology but may represent an upstream mechanism linking diverse risk factors to the development of the disease.
Human Data: Correlation Rather than Causation
While human studies cannot yet confirm a direct causal relationship between glymphatic dysfunction and AD, multiple lines of correlative evidence are emerging.
Post-mortem studies reveal that patients with AD have reduced perivascular AQP4 localisation in brain regions associated with amyloid burden and cognitive decline. Importantly, this reduction in AQP4 polarity occurs even when total AQP4 expression remains unchanged, suggesting a specific loss of functional localisation rather than global downregulation.
Imaging studies using contrast-enhanced MRI have confirmed perivascular solute transport in the human brain and demonstrated that this transport is sleep-dependent. Sleep deprivation has been shown to impair CSF tracer clearance and increase concentrations of Aβ and tau in CSF. These findings mirror those from rodent studies and suggest that glymphatic transport mechanisms are conserved across species.
Genetic studies have identified single-nucleotide polymorphisms (SNPs) in the AQP4 gene that are associated with cognitive decline, sleep latency, and increased amyloid deposition in patients with Alzheimer’s disease. These polymorphisms may influence the efficiency of glymphatic clearance and could represent a genetic basis for inter-individual variability in disease progression.
Sleep, Solute Clearance, and Biomarker Dynamics
The Keil et al. review draws particular attention to the sleep dependency of glymphatic function. In both rodents and humans, sleep deprivation has been shown to raise interstitial concentrations of Aβ and tau, while reducing their appearance in the plasma. This suggests that impaired sleep inhibits clearance from the brain to the systemic circulation.
A crossover study cited in the review demonstrated that one night of sleep deprivation increased CSF concentrations of Aβ and tau by 35 to 55 percent and led to a reduction in plasma biomarker levels. These data support the hypothesis that poor sleep impairs solute clearance across the blood-brain barrier and may accelerate pathological accumulation in the brain.
This is particularly relevant in early Alzheimer’s, where sleep disturbances are common and may contribute to a self-reinforcing cycle of glymphatic dysfunction and neurodegeneration.
Relevance to Transcranial Pulse Stimulation (TPS)
Transcranial Pulse Stimulation (TPS) is a non-invasive neuromodulation therapy that uses ultrashort acoustic pulses to stimulate deep cortical and subcortical brain structures. Clinical studies have demonstrated improvements in cognitive function, regional brain perfusion, and resting-state connectivity following TPS in patients with mild to moderate Alzheimer’s disease.
Although TPS has not been studied specifically in the context of glymphatic modulation, several of its physiological effects are relevant:
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Cerebral perfusion: Glymphatic flow depends on arterial pulsatility. TPS increases local blood flow, which may restore or enhance this pulsatile drive.
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Astroglial and vascular activation: Improved neurovascular coupling may indirectly support AQP4 localisation and glial function, both of which are necessary for efficient solute transport.
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Potential effects on sleep: Some patients report improved sleep quality following TPS, though this remains anecdotal. If substantiated, such improvements may indirectly enhance glymphatic clearance.
Further research is required to determine whether TPS directly influences glymphatic transport. However, its known effects on vascular dynamics, neural synchrony, and functional network integrity provide a plausible mechanistic link.
Clinical Outlook and Research Directions
The authors of the Science review emphasise the need for validated, non-invasive tools to measure glymphatic function in humans. Techniques such as DTI-ALPS, intravoxel incoherent motion imaging, and quantitative arterial spin labelling are being developed but are not yet suitable for routine clinical use.
In parallel, pharmacological and behavioural interventions aimed at restoring AQP4 localisation, improving sleep, or modulating noradrenergic tone are under investigation. Device-based interventions that improve perfusion or synchronised low-frequency neural activity may also play a role.
Given the mechanistic overlap between TPS and several of these physiological targets, further investigation into its effects on solute clearance, particularly when combined with sleep and vascular assessments, is warranted.
Conclusion
The 2025 review by Keil et al. presents a detailed and critical synthesis of glymphatic research in Alzheimer’s disease. While causal relationships in humans remain unproven, the evidence linking impaired clearance with disease progression is strong and consistent. Glymphatic dysfunction may represent a shared mechanistic pathway through which multiple risk factors exert their effects.
Transcranial Pulse Stimulation, while not initially developed for this purpose, may align with several of the system’s physiological requirements. As the field moves toward earlier and more mechanism-based interventions, a better understanding of how TPS influences brain clearance pathways may support its broader use in the management of Alzheimer’s disease.
