Combined Dysfunction of Glymphatic System and Mitochondria: A Noval Causal Contributor to Alzheimer’s Disease?
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Published
Jul 31, 2025
Abstract
Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is traditionally attributed to amyloid-beta (Aβ) accumulation and tau pathology. However, emerging evidence suggests that broader systemic dysfunctions may underlie or contribute to these hallmark features. Two biological systems—the glymphatic clearance pathway and mitochondrial energy metabolism—have independently gained attention for their roles in neurodegeneration. The glymphatic system facilitates cerebrospinal fluid (CSF) flow and waste clearance, including Aβ, while mitochondria regulate neuronal bioenergetics and redox homeostasis. By interlinking impaired clearance of neurotoxins and disrupted cellular energy metabolism, a vicious cycle may emerge that accelerates cognitive decline. We argue that integrated dysfunction could serve as an upstream event contributing to disease onset and progression. Understanding this combined pathology may not only redefine causality in AD but also offer novel therapeutic strategies targeting the neurovascular-energetic interface.
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Keywords
Alzheimer’s Disease, Glymphatic System, Mitochondria, Combination Dysfunction, Homeostasis
Supporting Agencies
No funding source declared.
References
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Voumvourakis, K. I., Sideri, E., Papadimitropoulos, G. N., Tsantzali, I., Hewlett, P., Kitsos, D., Stefanou, M., Bonakis, A., Giannopoulos, S., Tsivgoulis, G., & Paraskevas, G. P. (2023). The Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep. Biomedicines, 11(8), 2092. https://doi.org/10.3390/biomedicines11082092
Xu, Z., Xiao, N., Chen, Y., Huang, H., Marshall, C., Gao, J., Cai, Z., Wu, T., Hu, G., & Xiao, M. (2015). Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Molecular Neurodegeneration, 10(1). https://doi.org/10.1186/s13024-015-0056-1
Yoo, R., Kim, J., Moon, H. Y., Park, J. Y., Cheon, S., Shin, H., Han, D., Kim, Y., Park, S., & Choi, S. H. (2025). Long-term physical exercise facilitates putative glymphatic and meningeal lymphatic vessel flow in humans. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-58726-1
Cai, Y., Zhang, Y., Leng, S., Ma, Y., Jiang, Q., Wen, Q., Ju, S., & Hu, J. (2024). The relationship between inflammation, impaired glymphatic system, and neurodegenerative disorders: A vicious cycle. Neurobiology of Disease, 192, 106426. https://doi.org/10.1016/j.nbd.2024.106426
Corbali, O., & Levey, A. I. (2025). Glymphatic system in neurological disorders and implications for brain health. Frontiers in Neurology, 16. https://doi.org/10.3389/fneur.2025.1543725
Dhariwal, R., Jain, M., Mir, Y. R., Singh, A., Jain, B., Kumar, P., Tariq, M., Verma, D., Deshmukh, K., Yadav, V. K., & Malik, T. (2025). Targeted drug delivery in neurodegenerative diseases: the role of nanotechnology. Frontiers in Medicine, 12. https://doi.org/10.3389/fmed.2025.1522223
Ding, Z., Fan, X., Zhang, Y., Yao, M., Wang, G., Dong, Y., Liu, J., & Song, W. (2023). The glymphatic system: a new perspective on brain diseases. Frontiers in Aging Neuroscience, 15. https://doi.org/10.3389/fnagi.2023.1179988
Fedele, E. (2023). Anti-Amyloid therapies for Alzheimer’s Disease and the Amyloid cascade hypothesis. International Journal of Molecular Sciences, 24(19), 14499. https://doi.org/10.3390/ijms241914499
Gao, Y., Liu, K., & Zhu, J. (2023). Glymphatic system: an emerging therapeutic approach for neurological disorders. Frontiers in Molecular Neuroscience, 16. https://doi.org/10.3389/fnmol.2023.1138769
Han, L. (2025). AD-Diff: enhancing Alzheimer’s disease prediction accuracy through multimodal fusion. Frontiers in Computational Neuroscience, 19. https://doi.org/10.3389/fncom.2025. 1484540
Jiang-Xie, L., Drieu, A., & Kipnis, J. (2024). Waste clearance shapes aging brain health. Neuron. https://doi.org/10.1016/j.neuron.2024.09.017
Johnson, E. C. B., Bian, S., Haque, R. U., Carter, E. K., Watson, C. M., Gordon, B. A., Ping, L., Duong, D. M., Epstein, M. P., McDade, E., Barthélemy, N. R., Karch, C. M., Xiong, C., Cruchaga, C., Perrin, R. J., Wingo, A. P., Wingo, T. S., Chhatwal, J. P., Day, G. S., . . . Ringman, J. (2023). Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease. Nature Medicine, 29(8), 1979–1988. https://doi.org/10.1038/s41591-023-02476-4
Jukkola, J., Kaakinen, M., Singh, A., Moradi, S., Ferdinando, H., Myllylä, T., Kiviniemi, V., & Eklund, L. (2024). Blood pressure lowering enhances cerebrospinal fluid efflux to the systemic circulation primarily via the lymphatic vasculature. Fluids and Barriers of the CNS, 21(1). https://doi.org/10.1186/s12987-024-00509-9
Kopeć, K., Szleszkowski, S., Koziorowski, D., & Szlufik, S. (2023). Glymphatic system and mitochondrial dysfunction as two crucial players in pathophysiology of neurodegenerative disorders. International Journal of Molecular Sciences, 24(12), 10366. https://doi.org/10.3390/ijms241210366
Kylkilahti, T. M., Berends, E., Ramos, M., Shanbhag, N. C., Töger, J., Bloch, K. M., & Lundgaard, I. (2021). Achieving brain clearance and preventing neurodegenerative diseases—A glymphatic perspective. Journal of Cerebral Blood Flow & Metabolism, 41(9), 2137–2149. https://doi.org/10.1177/0271678x20982388
Lin, X., Fan, Y., Zhang, F., & Lin, Y. (2022). Cerebral microinfarct is emergency consequence of Alzheimer’s disease: a new insight into development of neurodegenerative diseases. International Journal of Biological Sciences, 18(4), 1569–1579. https://doi.org/10.7150/ijbs.55419
Mestre, H., Tithof, J., Du, T., Song, W., Peng, W., Sweeney, A. M., Olveda, G., Thomas, J. H., Nedergaard, M., & Kelley, D. H. (2018). Flow of cerebrospinal fluid is driven by arterial pulsations and is reduced in hypertension. Nature Communications, 9(1). https://doi.org/10.1038/s41467-018-07318-3
Moreira, P. I., Zhu, X., Wang, X., Lee, H., Nunomura, A., Petersen, R. B., Perry, G., & Smith, M. A. (2009). Mitochondria: A therapeutic target in neurodegeneration. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease, 1802(1), 212–220. https://doi.org/10.1016/j.bbadis.2009.10.007
Reddy, O. C., & Van Der Werf, Y. D. (2020). The Sleeping Brain: Harnessing the Power of the Glymphatic System through Lifestyle Choices. Brain Sciences, 10(11), 868. https://doi.org/10.3390/brainsci10110868
San-Millán, I. (2023). The key role of mitochondrial function in health and disease. Antioxidants, 12(4), 782. https://doi.org/10.3390/antiox12040782
Shinn, L. J., & Lagalwar, S. (2021). Treating Neurodegenerative Disease with Antioxidants: Efficacy of the Bioactive Phenol Resveratrol and Mitochondrial-Targeted MitoQ and SkQ. Antioxidants, 10(4), 573. https://doi.org/10.3390/antiox10040573
Silva, J., Alves, C., Soledade, F., Martins, A., Pinteus, S., Gaspar, H., Alfonso, A., & Pedrosa, R. (2023). Marine-Derived Components: Can they be a potential therapeutic approach to Parkinson’s disease? Marine Drugs, 21(8), 451. https://doi.org/10.3390/md21080451
Voumvourakis, K. I., Sideri, E., Papadimitropoulos, G. N., Tsantzali, I., Hewlett, P., Kitsos, D., Stefanou, M., Bonakis, A., Giannopoulos, S., Tsivgoulis, G., & Paraskevas, G. P. (2023). The Dynamic Relationship between the Glymphatic System, Aging, Memory, and Sleep. Biomedicines, 11(8), 2092. https://doi.org/10.3390/biomedicines11082092
Xu, Z., Xiao, N., Chen, Y., Huang, H., Marshall, C., Gao, J., Cai, Z., Wu, T., Hu, G., & Xiao, M. (2015). Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Molecular Neurodegeneration, 10(1). https://doi.org/10.1186/s13024-015-0056-1
Yoo, R., Kim, J., Moon, H. Y., Park, J. Y., Cheon, S., Shin, H., Han, D., Kim, Y., Park, S., & Choi, S. H. (2025). Long-term physical exercise facilitates putative glymphatic and meningeal lymphatic vessel flow in humans. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-58726-1
How to Cite
Gaber, F. (2025). Combined Dysfunction of Glymphatic System and Mitochondria: A Noval Causal Contributor to Alzheimer’s Disease?. Science Insights, 47(1), 1883–1887. https://doi.org/10.15354/si.25.pe245
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