Brain’s Waste Clearance System Implicated in Dementia

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Brain’s Waste Clearance System Implicated in Dementia

Impaired glymphatic function — the brain’s waste clearance system — could help explain how cardiovascular disease (CVD) risk factors may drive dementia. 

In a large UK Biobank study, MRI markers of disrupted cerebrospinal fluid (CSF) and glymphatic flow predicted future dementia and were closely linked to vascular risk factors, including high blood pressure, diabetes, smoking, and arterial stiffness.

Discovered just over a decade ago, the glymphatic system depends on the efficient circulation and drainage of CSF. When this process is impaired, the brain’s ability to clear amyloid, tau, and other toxins diminishes, potentially accelerating the development of dementia.

“The study shows, with very convincing data, that these markers predict dementia risk, and also that the markers relate to cardiovascular risk factors,” study author Hugh S. Markus, MD, professor of stroke medicine in the Department of Clinical Neurosciences, University of Cambridge, UK, told Medscape Medical News.

“This offers a novel way in which one might be able to target or treat dementia. If one could improve glymphatic flow, one could then reduce the risk of dementia.”The study results were published online on October 23 in Alzheimer's & Dementia and simultaneously presented at the 17th World Stroke Congress (WSC) 2025 in Barcelona, Spain. 

Human Glymphatic Function Revealed

Over the years, studies in animal models of dementia and cerebral small-vessel disease have helped clarify how the glymphatic system functions. 

As the authors explain, CSF is continuously produced by the choroid plexus (CP), creating pressure that drives its flow from the brain’s ventricles into the subarachnoid space. From there, CSF enters the brain tissue via perivascular spaces (PVS), where it exchanges with interstitial fluid. This exchange facilitates the clearance of metabolic waste from the brain through the PVS.

Until recently, glymphatic function could be studied only in mice. Advances in MRI now make it possible to assess this system indirectly in humans. Researchers are using machine learning-based methods to quantify imaging markers of glymphatic function across large populations.

“We applied these techniques to see whether glymphatic drainage in the brain was impaired in people who had cardiovascular risk factors or had small-vessel disease of the brain, and, particularly importantly, to see whether this predicted dementia,” said Markus.

MRI-Based Biomarkers

The researchers examined several MRI-based biomarkers that serve as proxies for CSF and glymphatic dynamics. These included:

• PVS volume, reflecting the size of the small channels that run alongside blood vessels
• Diffusion tensor imaging–analysis along the PVS (DTI-ALPS), which measures the movement of water molecules along perivascular spaces — higher values indicate more efficient CSF clearance
• Blood oxygen level–dependent CSF (BOLD–CSF) coupling, which captures the relationship between cerebral blood flow and CSF inflow from the spinal cord into the brainstem — impaired coupling signals reduced CSF and glymphatic flow
• CP volume, as enlargement of the CP has been linked to decreased CSF production and waste clearance

The study included 44,384 participants (median age, 65 years; 47.9% male) with available MRI data. Over a median follow-up of 5.3 years, 133 participants developed dementia. Higher baseline DTI-ALPS values were associated with a lower risk for dementia after adjustment for age, sex, and education (hazard ratio [HR], 0.866; 95% CI, 0.797-0.942; P = .001).

Higher CP volume predicted dementia conversion (corrected HR, 1.185; 95% CI, 1.088-1.291; P < .001), as did lower BOLD-CSF coupling (corrected HR, 0.875; 95% CI, 0.806-0.951; P = .001).

However, PVS volume did not predict dementia conversion (corrected HR 1.013; 95% CI 0.940-1.091; P = .730).

Vascular Damage Impairs Brain Cleanup

All major CVD risk factors were associated with signs of impaired glymphatic flow across multiple imaging markers. Higher systolic blood pressure, for instance, correlated with larger PVS volume, lower DTI-ALPS, higher CP volume, and weaker BOLD-CSF coupling (P <.001 for all). Diabetes showed a similar pattern, with lower DTI-ALPS, higher CP volume, and reduced BOLD-CSF coupling, although it was not associated with PVS volume.

When the researchers examined potential mediators of dementia risk, diabetes emerged as particularly important, said Markus. Both DTI-ALPS and CP volume partially mediated the associations between white-matter hyperintensities and dementia, as well as between diabetes duration and dementia. 

The imaging markers were also linked to measures of cardiac and arterial function — including maximum carotid intima-media thickness, left ventricular ejection fraction, and arterial stiffness — though the strength of these associations varied.

The findings shed light on how CVD risk factors could contribute to dementia. Conditions such as hypertension and diabetes can damage the brain’s small blood vessels, leading in turn to glymphatic dysfunction, Markus said.

In addition to the vascular risk factors examined in the study, impaired sleep can also disrupt the brain’s waste-clearance system, Markus noted. It has been suggested that poor sleep is an important factor that interferes with glymphatic function and reduces the clearance of toxins from the brain, he said. 

With a clearer picture of the pathologic processes driving dementia, the next step is to identify ways to target the glymphatic system to reduce risk. Markus pointed to emerging research testing investigational agents designed to restore or enhance the brain’s natural waste clearance function.

Aside from controlling blood pressure, there are at present few effective treatments for vascular dementia, which results from reduced blood flow to the brain, Markus said. The same is true for Alzheimer’s disease, where antiamyloid therapies “don’t help all that much,” he added. 

Lifestyle Matters

Commenting on the research for Medscape Medical News, Ozama Ismail, PhD, director of scientific programs at the Alzheimer’s Association, said the study helps clarify the complex relationships among vascular changes in the brain, removal of harmful waste, and incident dementia.

“In this way, it may help us identify future targets for treatment and risk reduction,” he said.

Ismail added that research has consistently shown a close link between heart health and brain health and noted that the Alzheimer’s Association’s US POINTER study recently demonstrated that a heart-healthy diet and regular exercise can help delay cognitive decline in individuals at increased risk. 

Researchers plan to incorporate in-home sleep assessments into a US POINTER substudy to examine whether lifestyle changes can improve sleep. The glymphatic system appears to be most active during sleep, Ismail noted.

The study was supported by the British Heart Foundation, Cambridge British Heart Foundation Centre of Research Excellence, Cambridge University Hospitals National Institute for Health and Care Research Biomedical Research Centre. Markus reports no relevant conflicts of interest.