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Impairment of paravascular clearance pathways in the aging brain
Open accessAbstract
Objective: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF–ISF exchange and interstitial solute clearance is impaired in the aging brain. Methods: CSF–ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2–3 months), middle‐aged (10–12 months), and old (18–20 months) wild‐type mice. The relationship between age‐related changes in the expression of the astrocytic water channel aquaporin‐4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. Results: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid‐β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF–ISF exchange. Interpretation: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates. Ann Neurol 2014;76:845–861
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“In AD, reactive astrogliosis is upregulated corresponds to the severity of astroglial activation and high levels of proinflammatory cytokines and the hypertrophic processes make aberrant contacts with nearby cerebral vessels and neurons, leading to neurovascular uncoupling.[ 42 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [42]
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“Impaired glymphatic function has been suggested to be instrumental in a range of brain diseases; this has been illustrated most in Alzheimer's dementia (7, 19, 20) but has also been shown to be relevant in posttraumatic encephalopathy (21), ageing (22), sleep (23, 24), depression (20), and exercise (25).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [22]
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In the citing paper
“and paravascular clearance has been shown to be impaired with ageing (22).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [22]
In the citing paper
“Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“Aging is also associated with a steep fall in glymphatic flow in the brains of both rodents and humans.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“CSF inflow of larger tracers are reduced by up to 85% in aged wild-type mice”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“The decrease in glymphatic flow in old mice is in part mediated by mislocation of AQP4 water channels away from the vascular wall (52) and possible by atrophy of meningeal lymphatic vessel (42).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“while contrast clearance in human brain tissue was inversely correlated to age in all subjects studied (50, 52–54).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
In the citing paper
“As individuals age, there is a decline in the efficiency of these transport mechanisms in eliminating waste products such as Aβ.156,157”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [157]
In the citing paper
“both the brain glymphatic and meningeal lymphatic systems deteriorate with age”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Kress et al., 2014
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Self-citationCircadian Mechanisms in Brain Fluid Biology
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“…CSF clearance in aged mice has been partly attributed to dysregulation of astroglial water transport due to the widespread loss of AQP4 polarization (Kress et al., 2014), the decline of CSF pressure (Fleischman et al., 2012), and the changes of CSF secretion and protein content (Chen et al., 2009).”
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“A decrease in the density of these channels in the perivascular endfeet affects clearance of the brain parenchyma through the glymphatic pathway [42].”
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“Other studies suggested a controversial opinion, in that the depletion of astrocytic AQP4 caused water to accumulate in the brain (34) and markedly impaired interstitial solute clearance (38).”
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“39,49 Additionally, during inflammation, many inflammatory cells infiltrate and accumulate in the perivascular space, which may physically block lymphatic transport.”
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“Aging, stroke, and traumatic brain injury have all been shown to depolarize the polarized state of AQP4 (Iliff et al., 2012; Iliff et al., 2014; Gaberel et al., 2014; Kress et al., 2014).”
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“As the previous methods [62, 63], the median immuno fl uores-cence intensity of perivascular regions was measured to measure perivascular AQP4 polarization.”
MethodNeuroimmune and neuroinflammation response for traumatic brain injury
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“The end-foot of astrocytes densely expresses aquaporin 4 (AQP4), which fosters the entry of CSF into the brain parenchyma, in which it mixes of interstitial fluids (Iliff et al., 2012; Kress et al., 2014).”
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“Aging astrocytes become hypertrophic (155) and display lower AQP4 expression (156).”
BackgroundEffect of intravoxel incoherent motion on diffusion parameters in normal brain
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“11.”
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“Moreover, the interaction of sex and age with tau pathology after TBI is an area that has not been investigated before, although Tau aggregation after TBI is associated with impaired glymphatic function, which also reduces with age (Iliff et al., 2014; Kress et al., 2014).”
BackgroundJacobsen, H. H., Sandell, T., Jørstad, Ø. K., Moe, M. C., Ringstad, G. A., & Eide, P. K. (2020) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.61.13.24 · Cited by 28
“49 It is therefore possible that some of the differences between the groups represent age effects.”
The Impact of Ageing on the CNS Immune Response in Alzheimer’s Disease
Chee, S. E. J., & Solito, E. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.738511 · Cited by 29
“However, a loss of this polarization of AQP4 channels from the end-feet to the parenchymal processes instead has been observed in AD (44).”
BackgroundA novel conceptual framework for the functionality of the glymphatic system
Astara, K., Pournara, C., de Natale, E. R., Wilson, H., Vavougios, G. D., Lappas, A. S., Politis, M., & Christodoulou, G. N. (2023) · Journal of Neurophysiology · doi:10.1152/jn.00360.2022 · Cited by 30
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“89 AQP-4 expression during inflammation is upregulated; however, loss of vascular AQP-4 polarization leads to decrease of glymphatic flow, because the additional AQP-4 channels are inserted in the cell body and peri-synaptic processes of astrocytes, rather than in their vascular endfeet, which sheath the PVS. 72 Final…”
BackgroundInfluentialCerebrospinal fluid turnover as a driver of brain clearance
Smets, N. G., Strijkers, G. J., Vinje, V., & Bakker, E. N. T. P. (2023) · NMR in Biomedicine · doi:10.1002/nbm.5029 · Cited by 28
“8 These and many other findings suggest an important link between impaired AQP4 functioning and reduced brain clearance.”
BackgroundDysfunction of the glymphatic system in childhood absence epilepsy
Pu, W., Wei, S., Qiu, M., Chen, X., Zou, W., Ge, Y., & Qiu, W. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1312676 · Cited by 28
“…beyond the age of 40 in adults, a negative correlation is observed (McKnight et al., 2021; Lee et al., 2022a,b), as the number of polarized aquaporin-4 channels on the end feet of astrocyte cells and CSF production decrease along with arterial pulsatility (Kress et al., 2014; Jessen et al., 2015).”
BackgroundLi, M., Xu, J., Li, L., Zhang, L., Zuo, Z., Feng, Y., He, X., & Hu, X. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114770 · Cited by 28
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“Impaired glymphatics [51] has also been shown to be increased with age and precedes significant Aβ deposits, further indicating the importance of CSF outflow into the lymphatics as a significant factor in the development of AD [52].”
RETRACTED: The effects of antimony on Alzheimer's disease-like pathological changes in mice brain
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“CSF facilitates exchange through multiple flow routes — it travels down the spinal cord, and it enters the glymphatic space and the subarachnoid space (29, 30).”
MRI-Based Demonstration of the Normal Glymphatic System in a Human Population: A Systematic Review
Lee, M. K., Cho, S. J., Bae, Y. J., & Kim, J. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.827398 · Cited by 28
Engrafted glial progenitor cells yield long-term integration and sensory improvement in aged mice
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“of perivascular AQP4 in the aged neocortex Ageing causes degeneration of astrocytic endfeet [28] and depolarization of perivascular AQP4 [29], resulting in prominent neurovascular dysfunction [28] and the accumulation of protein waste [29].”
BackgroundSelf-citationDynamic Evolution of the Glymphatic System at the Early Stages of Subarachnoid Hemorrhage
Hou, C., Li, J., Wang, B., Liu, Q., Zhao, Y., Zhang, H., Wang, W., Ren, W., Cui, X., & Yang, X. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.924080 · Cited by 27
“Neuroinflammation and reactive astrogliosis are prominent features of SAH, and reactive astrogliosis is generally associated with the loss of AQP4 expression (14).”
BackgroundMethodLiver X Receptor Regulation of Glial Cell Functions in the CNS
Song, X., Wu, W., Warner, M. N., & Gustafsson, J.-Α. (2022) · Biomedicines · doi:10.3390/biomedicines10092165 · Cited by 28
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“Glymphatic dysfunction has been demonstrated in aging rodent brain [13] and could potentially lead to Aβ accumulation, a hallmark of AD pathology [14].”
BackgroundÖzşahin, İ., Zhou, L., Wang, X. H., Garetti, J., Jamison, K. W., Xi, K., Tanzi, E. B., Jaywant, A., Patchell, A., Maloney, T., et al. (2024) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230143 · Cited by 29
Chen, Y., Guo, H., Sun, X., Wang, S., Zhao, M., Gong, J., He, A., Li, J., Liu, Y., & Wang, Z. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70289 · Cited by 27
“AQP4 polarization was assessed on day 3 post-ICH [12, 33].”
Chen, K., Morizawa, Y. M., Nuriel, T., Al‐Dalahmah, O., Xie, Z., & Yang, G. (2025) · Neuron · doi:10.1016/j.neuron.2025.04.027 · Cited by 27
Yang, Z., Zhang, X., Li, C., Chi, S., & Xie, A. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.592989 · Cited by 28
Glymphatic system dysfunction in patients with early chronic kidney disease
Heo, C. M., Lee, D. A., Park, K. M., Lee, Y. J., Park, S., Kim, Y. W., Ko, J., Yoo, B. C., & Park, B. S. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.976089 · Cited by 27
“Previous studies have shown a decrease in glymphatic activity during aging (30, 31).”
BackgroundSepehrinezhad, A., Larsen, F. S., Ahmadabad, R. A., Shahbazi, A., & Negah, S. S. (2023) · Cells · doi:10.3390/cells12070979 · Cited by 25
Saito, Y., Kamagata, K., Andica, C., Taoka, T., Tuerxun, R., Uchida, W., Takabayashi, K., Owaki, M., Yoshida, S., Yamazaki, K., et al. (2023) · Japanese Journal of Radiology · doi:10.1007/s11604-023-01432-z · Cited by 26
“The glymphatic hypothesis [1, 2] states that the subarachnoid cerebrospinal fluid (CSF) enters the brain interstitial space from the periarterial space via the aquaporin-4 channel expressed in astrocyte end-feet and then mixes with the interstitial fluid (ISF) and waste solutes in the brain.”
Wu, H., Liu, B., Liu, W. V., Wen, Z., Yang, W., Yang, H., Li, J., & Zha, Y. (2025) · Schizophrenia · doi:10.1038/s41537-025-00661-7 · Cited by 25
“Consistent with prior research, we observed a negative correlation between age and DTI-ALPS indices in HCs, indicating an age-related decline in glymphatic function 33,34 .”
Bedolla, A., Taranov, A., Luo, F., Wang, J., Turcato, F., Fugate, E. M., Greig, N. H., Lindquist, D. M., Crone, S. A., Goto, J., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02367-w · Cited by 25
Fluid dynamics in aging-related dementias
Bah, T. M., Siler, D. A., Ibrahim, A. H., Cetas, J. S., & Alkayed, N. J. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105986 · Cited by 26
“In aging mice, glymphatic function is slowed with a reduction in the clearance of A β (Kress et al., 2014), and diffuse ischemic lesions impair glymphatic function in a mouse model of microinfarcts (Wang et al., 2017).”
InfluentialMultifaceted Roles of Aquaporins in the Pathogenesis of Alzheimer’s Disease
Yamada, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076528 · Cited by 26
“The impairment of glymphatic clearance has been implicated in aged brains and many neurodegenerative diseases [43,44].”
BackgroundPark, K. M., Kim, K. T., Lee, D. A., Motamedi, G. K., & Cho, Y. W. (2023) · SLEEP · doi:10.1093/sleep/zsad239 · Cited by 25
Aβ Clearance, “hub” of Multiple Deficiencies Leading to Alzheimer Disease
Gallina, P., Scollato, A., Conti, R., Lorenzo, N. D., & Porfirio, B. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00200 · Cited by 25
“Aging has been associated with a drastic decline in the efficiency of exchange between the subarchnoidal CSF and brain parenchyma due to both a reduction in penetrating arterial pulsatility and altered Aqp4 expression within astrocytes (Kress et al., 2014).”
BackgroundZhang, C., Lin, J., Wei, F., Song, J. H., Chen, W., Shan, L., Xue, R., Wang, G., Tao, J., Zhang, G., et al. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.03.057 · Cited by 24
High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease
Pedrini, S., Chatterjee, P., Hone, E., & Martins, R. N. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15170 · Cited by 22
“The glymphatic/meningeal lymphatic waste collection system is mostly active during sleep and reduced functions have been observed in aged mice (Iliff et al., 2013; Kress et al., 2014; Xie et al., 2013).”
BackgroundNewton, P., the BIOCARD Research Team, Tchounguen, J., Pettigrew, C., Lim, C., Lin, Z., Lu, H., Moghekar, A., Albert, M., & Soldan, A. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-220846 · Cited by 23
Coupled pulsatile vascular and paravascular fluid dynamics in the human brain
Wright, A. M., Wu, Y., Yang, H., Risacher, S. L., Saykin, A. J., Tong, Y., & Wen, Q. (2024) · Fluids and Barriers of the CNS · doi:10.1186/s12987-024-00572-2 · Cited by 27
“Studies in mice suggest that aging is associated with a decrease in both vessel wall pulsa-tility and CSF clearance [11, 14].”
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Loss of glymphatic homeostasis in heart failure
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“9,10,38 To investigate whether heart failure affects AQP4 polarization, the polarization index was calculated 39,40 in different brain regions of MI and sham mice.”
InfluentialSelf-citationGenome-wide association study unravels mechanisms of brain glymphatic activity
Huang, S., Ge, Y., Ren, P., Wu, B., Gong, W., Du, J., Chen, S.-D., Kang, J., Ma, Q., Bokde, A. L. W., et al. (2025) · Nature Communications · doi:10.1038/s41467-024-55706-9 · Cited by 30
“…genetic correlations between ALPS-index and other neuropsychiatric phenotypes and vascular risk factors, including putative risk factors, cognition, neuropsychiatric and neurological disorders, CSF biomarkers of AD, and MRI-markers of cerebral small vessel disease (cSVD) (Supplementary Data 25).”
Reduced glymphatic clearance in early psychosis
Hua, L., Zeng, X., Zhang, K., Zhao, Z., & Yuan, Z. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03058-1 · Cited by 25
Fibrosis of the Choroid Plexus Filtration Membrane
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Cerebrovascular alterations in NAFLD: Is it increasing our risk of Alzheimer's disease?
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β-Amyloid and Tau Imaging in Chronic Traumatic Brain Injury
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The neuroimmune system – Where aging and excess alcohol intersect
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The Brain’s Glymphatic System: Drawing New Perspectives in Neuroscience
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“When sleeping naturally, brain interstitial space vastly expands compared to wakefulness—possibly as a result of astroglial cell shrinkage [38,44].”
BackgroundNon-invasive enhancement of intracortical solute clearance using transcranial focused ultrasound
Yoo, S., Kim, E., Kowsari, K., Reet, J. V., Kim, H., & Yoon, K. (2023) · Scientific Reports · doi:10.1038/s41598-023-39640-2 · Cited by 24
Visit-to-visit blood pressure variability and future functional decline in old age
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“Furthermore, recent studies suggest that inadequate cerebral perfusion may reduce the paravascular clearance of amyloid-b42 from the brain, thus favouring the development of neurodegenerative diseases [34,35].”
BackgroundCerebral microvascular abnormalities in patients with idiopathic intracranial hypertension
Eidsvaag, V. A., Hansson, H., Heuser, K., Nagelhus, E. A., & Eide, P. K. (2018) · Brain Research · doi:10.1016/j.brainres.2018.02.017 · Cited by 24
Glucose signaling in the brain and periphery to memory
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“Previous studies have shown that agerelated dysregulation of Aqp4 expression impairs its waste clearance function (Kress et al. 2014), and the amount of eliminated waste, including amyloid b of which accumulation cause dementia like Alzheimer’s disease, is reduced in the brain of Aqp4 knockout mice…”
BackgroundAstrocyte regulation of extracellular space parameters across the sleep-wake cycle
Sriram, S., Carstens, K., Dewing, W., & Fiacco, T. A. (2024) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1401698 · Cited by 29
Long-Term High-Fat Diet Impairs AQP4-Mediated Glymphatic Clearance of Amyloid Beta
Peng, W., Yuan, Y., Lei, J., Zhao, Y., Li, Y., Qu, Q., & Wang, J. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04320-3 · Cited by 24
“We adapted the methodology for calculating the polarization of the AQP4 index in the cortex, building upon previous protocols [38–40].”
Li, H., Yao, Q., Huang, X., Yang, X., & Yu, C. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1474439 · Cited by 26
The influence of the glymphatic system on α-synuclein propagation: the role of aquaporin-4
Lopes, D. M., Llewellyn, S. K., Bury, S. E., Wang, J., Wells, J. A., Gegg, M. E., Verona, G., Lythgoe, M. F., & Harrison, I. F. (2025) · Brain · doi:10.1093/brain/awaf255 · Cited by 27
Kato, Y., Bokura, K., Taoka, T., & Naganawa, S. (2019) · Japanese Journal of Radiology · doi:10.1007/s11604-019-00828-0 · Cited by 24
Aberrant waste disposal in neurodegeneration: why improved sleep could be the solution
Wafford, K. A. (2021) · Cerebral Circulation - Cognition and Behavior · doi:10.1016/j.cccb.2021.100025 · Cited by 25
“Other recent studies have demonstrated impairment of CSF tracer influx in aged mice, as well as reduced clearance of 125I-β-amyloid, suggesting that glymphatic function declines with increased age [69].”
Background
Metadata
- Authors
- Kress, B. T., Iliff, J. J., Xia, M., Wang, M., Wei, H. S., Zeppenfeld, D., Xie, L., Kang, H., Xu, Q., Liew, J. A., Plog, B. A., Ding, F., Deane, R., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- Oregon Health & Science University (US)
- Corresponding author
- Iliff, Jeffrey J.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2014-09-26
- Volume
- 76
- Issue
- 6
- Pages
- 845-861
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4245362
- OpenAlex
- W2100314515
- Cited by
- 1,521
- References
- 42
- Citations by year
- 2026: 182 · 2025: 186 · 2024: 202 · 2023: 167 · 2022: 172 · 2021: 126 · 2020: 126 · 2019: 98 · 2018: 89 · 2017: 70 · 2016: 54 · 2015: 47 · 2014: 1
- FWCI
- 26.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (12SDG11820014)
- National Institutes of Health (F32 NS073373)
- Oregon Partnership for Alzheimer's Research
- Topics
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- glymphatic system, brain aging, aquaporin-4, astrocytes, amyloid-beta clearance, cognitive decline, neurodegenerative diseases
- MeSH terms
- Aging, Animals, Brain, Cerebrovascular Circulation, Female, Male, Metabolic Clearance Rate, Mice, Inbred C57BL, Neuroglia, Microscopy, Fluorescence, Multiphoton, Mice, Aquaporin 4
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