How Glymphatic System Dysfunction May Drive Alzheimer’s Disease
- Ciatrix Research Team
- May 7
- 4 min read
Updated: May 7
A major advancement in the understanding of Alzheimer’s disease has emerged from a recent imaging study published in Brain Research Bulletin.
Researchers have identified a strong link between impaired brain perfusion, glymphatic system dysfunction, and cognitive decline: findings that may redefine how and when we diagnose the disease.
This discovery deepens our understanding of Alzheimer’s pathology and highlights the importance of the brain’s waste clearance system, the glymphatic system, in maintaining neurological health.
The Glymphatic System: A Crucial Mechanism in Brain Maintenance
Though still unfamiliar to much of the public, the glymphatic system has become a focal point in neuroscience since its discovery in 2012.
This system acts as the brain’s internal cleansing network, responsible for removing toxins and metabolic waste, including the beta-amyloid and tau proteins that accumulate in Alzheimer’s disease.
This system operates through a coordinated flow of cerebrospinal fluid (CSF) and interstitial fluid, which flushes waste from brain tissue. Waste-laden fluid is then transported out of the brain via perivenous spaces and meningeal lymphatic vessels, ultimately draining into the body’s lymphatic circulation.
Peak glymphatic activity occurs during deep, non-REM sleep and is further enhanced by spinal movements and diaphragmatic breathing. Activities such as yoga, qigong, and structured relaxation may therefore contribute to more efficient brain waste clearance.
As the system becomes less efficient with age and in response to poor sleep, stress, or vascular damage. Its dysfunction appears to play a direct role in the development of Alzheimer’s and other neurodegenerative conditions.
The Study: Simultaneous PET/MR Imaging Sheds New Light
In this new study, researchers used hybrid PET/MR imaging to simultaneously assess both early-phase beta-amyloid perfusion and glymphatic system function in three participant groups: healthy controls, individuals with prodromal Alzheimer’s disease (PAD), and patients with confirmed Alzheimer’s.
Two key findings emerged:
Glymphatic dysfunction, measured using the ALPS-index, was already present in the PAD group—individuals not yet diagnosed with dementia.
Perfusion deficits—reduced blood flow to critical memory-related areas such as the hippocampus—were significantly more pronounced in Alzheimer’s patients.
The ALPS-index (Analysis along the Perivascular Space) is a non-invasive MRI-based measure of glymphatic function. Lower values indicate reduced clearance activity, and in this study, ALPS-index values were significantly lower in both PAD and AD groups compared to healthy controls.
Importantly, the ALPS-index was also strongly correlated with cognitive performance, suggesting that reduced glymphatic clearance is a key contributor to cognitive decline, not merely a secondary effect.
Why This Matters: A Shift in Early Detection
These findings suggest that glymphatic dysfunction is one of the earliest detectable physiological changes in the Alzheimer’s continuum—preceding even the onset of major perfusion deficits or overt memory symptoms.
This discovery offers substantial clinical implications. If glymphatic dysfunction can be identified in the prodromal phase, it may be possible to intervene before irreversible damage occurs. This supports the growing case for incorporating dual-phase PET/MR imaging into early diagnostic protocols.
The research also reinforces the glymphatic system’s potential role as a clinical biomarker. Unlike traditional Aβ burden measures, which may remain stable over long periods, ALPS-index measurements can reflect dynamic physiological changes that closely track disease progression.
The Vascular Component: How Blood Flow Impacts Brain Cleansing
The study also examined the impact of vascular burden—damage to small blood vessels in the brain, commonly seen with aging. Vascular abnormalities, particularly white matter hyperintensities (WMH) and enlarged perivascular spaces (PVS), were more prevalent in Alzheimer’s patients and shown to mediate the relationship between glymphatic dysfunction and cognitive decline.
This illustrates a feedback loop: poor blood flow compromises glymphatic clearance, and impaired clearance exacerbates the accumulation of toxic proteins, leading to further vascular injury and cognitive deterioration.
These findings emphasize that Alzheimer’s is not solely a disease of protein deposition, but also one of vascular and clearance system failure.
Supporting Glymphatic Health: Evidence-Based Recommendations
While glymphatic dysfunction is not yet routinely assessed in clinical settings, there are evidence-based lifestyle factors that may enhance its activity:
Prioritize deep sleep: The glymphatic system is most active during non-REM sleep. Poor sleep is associated with reduced clearance and increased beta-amyloid levels.
Maintain hydration and support cardiovascular health, which directly influence CSF dynamics and perfusion.
Engage in regular physical activity, particularly practices that involve spinal mobilization and diaphragmatic breathing, such as yoga and qigong.
Reduce chronic stress, which can impair vascular function and limit the glymphatic system’s effectiveness.
Emerging interventions that target glymphatic flow—whether behavioral, pharmacological, or device-assisted—may offer new tools for prevention and disease modification.
The Ciatrix Perspective: Advancing a New Frontier in Alzheimer’s Research
At Ciatrix, we are committed to exploring the glymphatic system’s role in neurodegenerative disease and applying this knowledge to improve diagnostic tools, clinical outcomes, and quality of life. This new study reinforces the view that Alzheimer’s is a disease of early systemic breakdown, not just late-stage pathology.
By focusing on physiological systems like glymphatic clearance, we open the door to earlier detection, non-invasive monitoring, and personalized therapeutic strategies—well before irreversible damage occurs.
We believe that enhancing the brain’s natural self-maintenance mechanisms will define the future of brain health. We are exploring ways to enhance glymphatic activity. By harnessing this natural system, we aim to offer innovative solutions for improving brain health and general well-being.
References
Jiao, Y., et al. (2025). Characterization of the glymphatic system and early-phase β-amyloid imaging in Alzheimer's disease: A simultaneous PET/MR study. Brain Research Bulletin, 226, 111368. https://doi.org/10.1016/j.brainresbull.2025.111368
Iliff, J. J. & Wang, M. & Liao, Y. et al. (2012) A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Science Translational Medicine, 4(147), 147-111. http://dx.doi.org/10.1126/scitranslmed.3003748
Silva, I., Silva, J., Ferreira, R. et al. Glymphatic system, AQP4, and their implications in Alzheimer’s disease. Neurol. Res. Pract. 3, 5 (2021). https://doi.org/10.1186/s42466-021-00102-7
Hazzard I, Batiste M, Luo T, Cheung C, Lui F. Impaired glymphatic clearance is an important cause of Alzheimer’s disease. Explor Neuroprot Ther. 2024;4:401–10. https://doi.org/10.37349/ent.2024.00091
Wang Y, Zou W, Jin Z, Yin S, Chi X, Li J, Sun Y, Wu J, Kou L, Xia Y, Wang T. Sleep, glymphatic system, and Parkinson's disease. Ageing Neur Dis. 2024;4:6. http://dx.doi.org/10.20517/and.2023.56
Meng, JC., Shen, MQ., Lu, YL. et al. Correlation of glymphatic system abnormalities with Parkinson’s disease progression: a clinical study based on non-invasive fMRI. J Neurol 271, 457–471 (2024). https://doi.org/10.1007/s00415-023-12004-6