The DOI matches its Crossref record; 216 of the 216 references it cites were found in a registry or an index.
Clearance systems in the brain—implications for Alzheimer disease
Open accessAbstract
Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The concomitant BBB dysfunction not only reduces the intracerebral transport of glucose and other nutrients,[ 10 ] but also decreases the removal of excess metabolites,[ 11 ] thus alters the homeostasis in the central nervous system (CNS).”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The major reason for the accumulation of RAP‐RL along the cerebral microvasculature lies in that a key component of the nanostructure, RAP, a peptide derived from RAGE's nature ligand S100P, can specifically bind to RAGE overexpressing on the endothelium of AD cerebral vasculature.[ 15 , 38 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [15]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Moreover, the expression of AQP4 on astrocytic endfeet decrease and their perivascular polarization is inhibited, ultimately leading to lymphatic clearance dysfunction.[ 11 , 43 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [11]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Due to the lack of appropriate model systems, the role of LRP1 at the BBB and the overall relevance of BBB clearance are insufficiently understood and debated (4,7).”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [4]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In a healthy brain, Ab homeostasis is maintained by a balance between its production and clearance, whereas in AD brain overproduction and/or reduced clearance of Ab result in the formation of amyloid deposits (4).”
From Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia (2017) · cites this paper as [4]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Glial cells such as astrocytes and microglia also play a role in Aβ42 clearance by several mechanisms including proteolytic degradation of endocytosed proteins, clearance through the blood brain barrier, and clearance from to the CSF via the glymphatic pathway [46].”
From The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates (2020) · cites this paper as [46]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“An important clearance pathway for cerebral Aβ is the steady transport across the blood–brain barrier (BBB) [11].”
From PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier (2022) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Low Aβ levels within the healthy brain are maintained through degradation, elimination via interstitial fluid (ISF) bulk flow, cerebrospinal fluid (CSF) absorption into the circulatory and lymphatic system, or transport across the blood-brain barrier (BBB) (3,4).”
From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [4]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“RAP, a peptide derived from RAGE's nature ligand, S100B, can bind RAGE effectively.[ 15 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [15]
Experimental — accuracy not yet measuredIn the citing paper
“AQP4 levels are reduced in CAA; since AQP4 plays a vital role in glymphatic Aβ clearance in AD brain parenchyma, this consequently impairs Aβ clearance [606, 608].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [606]
In the citing paper
“AQP4 levels are reduced in CAA; since AQP4 plays a vital role in glymphatic Aβ clearance in AD brain parenchyma, this consequently impairs Aβ clearance [606, 608].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [606]
In the citing paper
“It has been suggested that vascular damage associated with CAA disrupts vascular drainage and homeostasis in the CNS, thereby impairing Aβ clearance and aggravating AD pathogenesis [606].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [606]
In the citing paper
“In contrast, Aβ peptides in the CNS can also move into the circulatory system, where the peptides are phagocytosed by the monocytes or neutrophils, directly degraded by the enzymes, or further transported to the peripheral organs or tissues for degradation or excretion.”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [28]
In the citing paper
“We and others have shown that both neurons and glia can clear extracellular Ab through endocytosis for subsequent lysosomal degradation or secretion of amyloiddegrading enzymes for extracellular clearance (4,7).”
From Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia (2017) · cites this paper as [4]
In the citing paper
“Impairment of Ab uptake and clearance by neurons, glia, and blood-brain-barrier endothelial cells may explain why the level of Ab is elevated and accumulates during AD progression (4).”
From Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia (2017) · cites this paper as [4]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Sperling, R. A., Aisen, P. S., Beckett, L. A., Bennett, D. A., Craft, S., Fagan, A. M., Iwatsubo, T., Jack, C. R., Kaye, J., Montine, T. J., et al. (2011) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2011.03.003 · Cited by 7,155
Iliff, J. J., Wang, M., Liao, Y., Plogg, B. A., Peng, W., Gundersen, G. A., Benveniste, H., Vates, G. E., Deane, R., Goldman, S. A., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003748 · Cited by 5,824
Sleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
Self-citationStructure and function of the blood–brain barrier
Abbott, N. J., Patabendige, A. A. K., Dolman, D. E. M., Yusof, S. R., & Begley, D. J. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.07.030 · Cited by 5,185
2016 Alzheimer's disease facts and figures
Alzheimer's Association (2016) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2016.03.001 · Cited by 5,069
Querfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569
Structural and functional features of central nervous system lymphatic vessels
Louveau, A., Smirnov, I., Keyes, T. J., Eccles, J. D., Rouhani, S. J., Peske, J. D., Derecki, N. C., Castle, D., Mandell, J. W., Lee, K. S., et al. (2015) · Nature · doi:10.1038/nature14432 · Cited by 4,413
Jack, C. R., Knopman, D. S., Jagust, W. J., Petersen, R. C., Weiner, M. W., Aisen, P. S., Shaw, L. M., Vemuri, P., Wiste, H. J., Weigand, S. D., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70291-0 · Cited by 4,396
Research works printed but not linked: 2
- Hetzel, L. 65 Years and Over Population: 2000. Census 2000 Brief (DIANE Publishing, 2008).
- Milford, H. in Studies in Intracranial Physiology and Surgery 1st edn Ch. 1 (ed. Cushing, H.) 1–50 (Oxford University Press, 1926).
Cited by
Sorted by citations
Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
Leng, F., & Edison, P. (2021) · Nature Reviews Neurology · doi:10.1038/s41582-020-00435-y · Cited by 3,179
Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders
Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2018) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.188 · Cited by 3,076
Self-citationThe Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease
Iadecola, C. (2017) · Neuron · doi:10.1016/j.neuron.2017.07.030 · Cited by 2,480
Blood-Brain Barrier: From Physiology to Disease and Back
Sweeney, M. D., Zhao, Z., Montagne, A., Nelson, A. R., & Zlokovic, B. V. (2019) · Physiological Reviews · doi:10.1152/physrev.00050.2017 · Cited by 2,312
Self-citationThe Cellular Phase of Alzheimer’s Disease
De Strooper, B., & Karran, E. (2016) · Cell · doi:10.1016/j.cell.2015.12.056 · Cited by 1,990
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Self-citationEstablishment and Dysfunction of the Blood-Brain Barrier
Zhao, Z., Nelson, A. R., Betsholtz, C., & Zlokovic, B. V. (2015) · Cell · doi:10.1016/j.cell.2015.10.067 · Cited by 1,670
Self-citationThe glymphatic pathway in neurological disorders.
Rasmussen, M. K., Mestre, H., & Nedergaard, M. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30318-1 · Cited by 1,560
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease
Guo, T., Zhang, D., Zeng, Y., Huang, T. Y., Xu, H., & Zhao, Y. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00391-7 · Cited by 994
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988
“CSF absorption clearance of Aβ depends on factors including CSF production by the choroid plexus, integrity of the blood-CSF barrier, relevant transporters and CSF lymphatic absorption.(28) In AD, the structural integrity of the blood-CSF barrier is destroyed, resulting in aberrant Aβ clearance.”
BackgroundCerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways
Greenberg, S. M., Bacskai, B. J., Hernandez-Guillamon, M., Pruzin, J., Sperling, R., & van Veluw, S. J. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-019-0281-2 · Cited by 947
Perivascular spaces in the brain: anatomy, physiology and pathology
Wardlaw, J. M., Benveniste, H., Nedergaard, M., Zlokovic, B. V., Mestre, H., Lee, H., Doubal, F. N., Brown, R., Ramirez, J., MacIntosh, B. J., et al. (2020) · Nature Reviews Neurology · doi:10.1038/s41582-020-0312-z · Cited by 870
Self-citationMeningeal lymphatic vessels at the skull base drain cerebrospinal fluid
Ahn, J. H., Cho, H., Kim, J.-H., Kim, S. H., Ham, J.-S., Park, I., Suh, S. H., Hong, S. P., Song, J.-H., Hong, Y.-K., et al. (2019) · Nature · doi:10.1038/s41586-019-1419-5 · Cited by 811
A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain
Wang, J., Gu, B. J., Masters, C. L., & Wang, Y.-J. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.111 · Cited by 808
APP mouse models for Alzheimer’s disease preclinical studies.
Sasaguri, H., Nilsson, P., Hashimoto, S., Nagata, K., Saito, T., De Strooper, B., Hardy, J., Vassar, R., Winblad, B., & Saido, T. C. (2017) · The EMBO Journal · doi:10.15252/embj.201797397 · Cited by 793
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
Iadecola, C., Yaffe, K., Biller, J., Bratzke, L. C., Faraci, F. M., Gorelick, P. B., Gulati, M., Kamel, H., Knopman, D. S., Launer, L. J., et al. (2016) · Hypertension · doi:10.1161/hyp.0000000000000053 · Cited by 746
Glymphatic MRI in idiopathic normal pressure hydrocephalus
Ringstad, G., Vatnehol, S. A. S., & Eide, P. K. (2017) · Brain · doi:10.1093/brain/awx191 · Cited by 722
Alzheimer’s disease: A matter of blood–brain barrier dysfunction?
Montagne, A., Zhao, Z., & Zlokovic, B. V. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20171406 · Cited by 672
Self-citationMa, Q., Ineichen, B. V., Detmar, M., & Proulx, S. T. (2017) · Nature Communications · doi:10.1038/s41467-017-01484-6 · Cited by 690
Interaction between Aβ and Tau in the Pathogenesis of Alzheimer’s Disease
Zhang, H., Wei, W., Zhao, M., Ma, L., Jiang, X., Pei, H., Cao, Y., & Li, H. (2021) · International Journal of Biological Sciences · doi:10.7150/ijbs.57078 · Cited by 689
Zeppenfeld, D. M., Simon, M., Haswell, J. D., D’Abreo, D., Murchison, C., Quinn, J. F., Grafe, M. R., Woltjer, R. L., Kaye, J., & Iliff, J. J. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2016.4370 · Cited by 651
Understanding the functions and relationships of the glymphatic system and meningeal lymphatics
Louveau, A., Plog, B. A., Antila, S., Alitalo, K., Nedergaard, M., & Kipnis, J. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90603 · Cited by 640
Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease
Nelson, A. R., Sweeney, M. D., Sagare, A. P., & Zlokovic, B. V. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.12.016 · Cited by 559
Self-citationEmerging concepts in sporadic cerebral amyloid angiopathy
Charidimou, A., Boulouis, G., Gurol, M. E., Ayata, C., Bacskai, B. J., Frosch, M. P., Viswanathan, A., & Greenberg, S. M. (2017) · Brain · doi:10.1093/brain/awx047 · Cited by 555
Mechanisms of Aβ Clearance and Degradation by Glial Cells
Ries, M., & Sastre, M. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00160 · Cited by 527
“Experimental data have suggested that Aβ and solutes can normally also be cleared along the lymphatic drainage pathways within the basement membranes of capillaries and arteries (Carare et al., 2008; Tarasoff-Conway et al., 2015).”
BackgroundEndothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier
Storck, S. E., Meister, S., Nahrath, J., Meißner, J. N., Schubert, N., Di Spiezio, A., Baches, S., Vandenbroucke, R. E., Bouter, Y., Prikulis, I., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci81108 · Cited by 477
Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
Da Mesquita, S., Papadopoulos, Z., Dykstra, T., Brase, L., Farias, F. G., Wall, M., Jiang, H., Kodira, C. D., de Lima, K. A., Herz, J., et al. (2021) · Nature · doi:10.1038/s41586-021-03489-0 · Cited by 431
Gorelick, P. B., Furie, K. L., Iadecola, C., Smith, E. E., Waddy, S. P., Lloyd-Jones, D. M., Bae, H.-J., Bauman, M. A., Dichgans, M., Duncan, P. W., et al. (2017) · Stroke · doi:10.1161/str.0000000000000148 · Cited by 411
Marsh, S. E., Abud, E. M., Lakatos, A., Karimzadeh, A., Yeung, S. T., Davtyan, H., Fote, G. M., Lau, L., Weinger, J. G., Lane, T. E., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525466113 · Cited by 411
Zou, W., Pu, T., Feng, W., Lu, M., Zheng, Y., Du, R., Xiao, M., & Hu, G. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0147-y · Cited by 396
Clusterin in Alzheimer’s Disease: Mechanisms, Genetics, and Lessons From Other Pathologies
Foster, E. M., Dangla-Valls, A., Lovestone, S., Ribe, E. M., & Buckley, N. J. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00164 · Cited by 381
Smith, A. J., Yao, X., Dix, J. A., Jin, B.-J., & Verkman, A. S. (2017) · eLife · doi:10.7554/elife.27679 · Cited by 362
Sharma, P., Srivastava, P., Seth, A., Tripathi, P. N., Banerjee, A. G., & Shrivastava, S. K. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.12.006 · Cited by 331
Ma, Q., Zhao, Z., Sagare, A. P., Wu, Y., Wang, M., Owens, N. C., Verghese, P. B., Herz, J., Holtzman, D. M., & Zlokovic, B. V. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0286-0 · Cited by 281
Self-citationFactors influencing the blood-brain barrier permeability
Zhao, Y., Gan, L., Ren, L., Lin, Y., Ma, C., & Lin, X. (2022) · Brain Research · doi:10.1016/j.brainres.2022.147937 · Cited by 291
Glial activation and inflammation along the Alzheimer’s disease continuum
Nordengen, K., Kirsebom, B.-E., Henjum, K., Selnes, P., Gísladóttir, B., Wettergreen, M., Torsetnes, S. B., Grøntvedt, G. R., Waterloo, K. K., Aarsland, D., et al. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1399-2 · Cited by 274
Normal tension glaucoma: review of current understanding and mechanisms of the pathogenesis
Killer, H., & Pircher, A. (2018) · Eye · doi:10.1038/s41433-018-0042-2 · Cited by 262
Mitochondria and Calcium in Alzheimer’s Disease: From Cell Signaling to Neuronal Cell Death
Calvo-Rodriguez, M., & Bacskai, B. J. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.10.004 · Cited by 254
Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides
Park, L., Uekawa, K., Garcia-Bonilla, L., Koizumi, K., Murphy, M., Pistik, R., Younkin, L., Younkin, S., Zhou, P., Carlson, G., et al. (2017) · Circulation Research · doi:10.1161/circresaha.117.311054 · Cited by 259
Amyloid-β Receptors: The Good, the Bad, and the Prion Protein
Jarosz-Griffiths, H. H., Noble, E., Rushworth, J. V., & Hooper, N. M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.702704 · Cited by 256
Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET
de Leon, M. J., Li, Y., Okamura, N., Tsui, W. H., Saint-Louis, L. A., Glodzik, L., Osorio, R. S., Fortea, J., Butler, T., Pirraglia, E., et al. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.116.187211 · Cited by 246
Self-citationCholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects
Feringa, F. M., & van der Kant, R. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.690372 · Cited by 226
Morris, G. P., Clark, I. A., & Vissel, B. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1918-8 · Cited by 212
Peripheral immune system in aging and Alzheimer’s disease
Cao, W., & Zheng, H. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0284-2 · Cited by 214
Early Alzheimer’s disease pathology in human cortex involves transient cell states
Gazestani, V., Kamath, T., Nadaf, N. M., Dougalis, A., Burris, S. J., Rooney, B., Junkkari, A., Vanderburg, C., Pelkonen, A., Gomez-Budia, M., et al. (2023) · Cell · doi:10.1016/j.cell.2023.08.005 · Cited by 209
Hladky, S. B., & Barrand, M. A. (2018) · Fluids and Barriers of the CNS · doi:10.1186/s12987-018-0113-6 · Cited by 206
Insulin-Degrading Enzyme in the Fight against Alzheimer's Disease
Kurochkin, I. V., Guarnera, E., & Berezovsky, I. N. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2017.10.008 · Cited by 185
Brain clearance is reduced during sleep and anesthesia
Miao, A., Luo, T., Hsieh, B., Edge, C. J., Gridley, M., Wong, R. T. C., Constandinou, T. G., Wisden, W., & Franks, N. P. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01638-y · Cited by 172
Chen, Y.-A., Lu, C.-H., Ke, C.-C., Chiu, S.-J., Jeng, F.-S., Chang, C.-W., Yang, B.-H., & Liu, R.-S. (2021) · Biomedicines · doi:10.3390/biomedicines9060594 · Cited by 167
Sundaram, S., Hughes, R. L., Peterson, E., Müller-Oehring, E. M., Brontë-Stewart, H. M., Poston, K. L., Faerman, A., Bhowmick, C., & Schulte, T. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.016 · Cited by 152
Sleep Disorders Associated With Alzheimer's Disease: A Perspective
Brzecka, A., Leszek, J., Ashraf, G. M., Ejma, M., Ávila-Rodriguez, M. F., Yarla, N. S., Tarasov, V. V., Chubarev, V. N., Samsonova, A. N., Barreto, G. E., et al. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00330 · Cited by 149
Feng, W., Zhang, Y., Wang, Z., Xu, H., Wu, T., Marshall, C., Gao, J., & Xiao, M. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00688-1 · Cited by 150
Boada, M., López, O. L., Olazarán, J., Núñez, L., Pfeffer, M., Paricio, M., Lorites, J., Piñol‐Ripoll, G., Gámez, J. E., Anaya, F., et al. (2020) · Alzheimer's & Dementia · doi:10.1002/alz.12137 · Cited by 143
Burfeind, K. G., Murchison, C. F., Westaway, S. K., Simon, M. J., Erten‐Lyons, D., Kaye, J. A., Quinn, J. F., & Iliff, J. J. (2017) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2017.05.001 · Cited by 136
Coles, J. A., Myburgh, E., Brewer, J. M., & McMenamin, P. G. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.05.002 · Cited by 123
HDL from an Alzheimer's disease perspective
Button, E. B., Robert, J., Caffrey, T. M., Fan, J., Zhao, W., & Wellington, C. L. (2019) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000604 · Cited by 114
Van Gool, B., Storck, S. E., Reekmans, S. M., Lechat, B., Gordts, P. L. S. M., Pradier, L., Pietrzik, C. U., & Roebroek, A. J. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1594-2 · Cited by 114
Tian, D.-Y., Cheng, Y., Zhuang, Z.-Q., He, C.-Y., Pan, Q.-G., Tang, M.-Z., Hu, X.-L., Shen, Y.-Y., Wang, Y.-R., Chen, S.-H., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01073-6 · Cited by 100
Glia in neurodegeneration: Drivers of disease or along for the ride?
Gleichman, A. J., & Carmichael, S. T. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104957 · Cited by 90
Vojtechova, I., Machacek, T., Kristofikova, Z., Stuchlik, A., & Petrasek, T. (2022) · PLOS Pathogens · doi:10.1371/journal.ppat.1010929 · Cited by 92
Riad, A., Lengyel-Zhand, Z., Zeng, C., Weng, C.-C., Lee, V. M.-Y., Trojanowski, J. Q., & Mach, R. H. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01988-1 · Cited by 81
Biomarkers for Alzheimer’s Disease
Guzman-Martinez, L., Maccioni, R. B., Farías, G. A., Fuentes, P., & Navarrete, L. P. (2019) · Current Alzheimer Research · doi:10.2174/1567205016666190517121140 · Cited by 87
Uekawa, K., Hattori, Y., Ahn, S. J., Seo, J., Casey, N., Anfray, A., Zhou, P., Luo, W., Anrather, J., Park, L., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00660-1 · Cited by 80
“There is increasing evidence that Aβ clearance depends on cerebrovascular health [2, 6, 13].”
InfluentialUllah, R., Park, T. J., Huang, X., & Kim, M. O. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101451 · Cited by 78
Basal lamina changes in neurodegenerative disorders
Nguyen, B., Bix, G., & Yao, Y. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00502-y · Cited by 75
Su, Q., Li, T., He, P.-F., Lu, X.-C., Yu, Q., Gao, Q.-C., Wang, Z.-J., Wu, M.-N., Yang, D., & Qi, J.-S. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00746-8 · Cited by 75
Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health
Katusic, Z. S., d’Uscio, L. V., & He, T. (2023) · Stroke · doi:10.1161/strokeaha.122.041444 · Cited by 73
Shim, H. S., Horner, J. W., Wu, C.-J., Li, J., Lan, Z. D., Jiang, S., Xu, X., Hsu, W.-H., Zal, T., Flores, I. I., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00146-z · Cited by 73
Lloret, M.-A., Cervera-Ferri, A., Nepomuceno, M., Monllor, P., Esteve, D., & Lloret, A. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031168 · Cited by 68
Central and peripheral circadian clocks and their role in Alzheimer's disease
Chauhan, R., Chen, K.-F., Kent, B. A., & Crowther, D. C. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.030627 · Cited by 58
Erratum: Clearance systems in the brain—implications for Alzheimer diseaser
Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B. V., et al. (2016) · Nature Reviews Neurology · doi:10.1038/nrneurol.2016.36 · Cited by 61
Self-citationImpact of increased APP gene dose in Down syndrome and the Dp16 mouse model
Sawa, M., Overk, C., Becker, A., Derse, D., Albay, R., Weldy, K., Salehi, A., Beach, T. G., Doran, E., Head, E., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12463 · Cited by 54
PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier
Mazura, A. D., Ohler, A., Storck, S. E., Kurtyka, M., Scharfenberg, F., Weggen, S., Becker-Pauly, C., & Pietrzik, C. U. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04237-x · Cited by 53
“To overcome the highly selective BBB most molecules require carrier- or receptor-mediated transport systems [12].”
BackgroundInfluentialAquaporin-4 and Cognitive Disorders
Wang, Y., Huang, C., Guo, Q., & Chu, H. (2022) · Aging and disease · doi:10.14336/ad.2021.0731 · Cited by 55
Calcium-Sensing Receptors of Human Neural Cells Play Crucial Roles in Alzheimer's Disease
Chiarini, A., Armato, U., Liu, D., & Dal Prà, I. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00134 · Cited by 51
Zhao, Z., Liu, Y., Ruan, S., & Hu, Y. (2023) · International Journal of Nanomedicine · doi:10.2147/ijn.s444115 · Cited by 49
Advanced Overview of Biomarkers and Techniques for Early Diagnosis of Alzheimer’s Disease
Rani, S., Dhar, S. B., Khajuria, A., Gupta, D., Jaiswal, P. K., Singla, N., Kaur, M., Singh, G., & Barnwal, R. P. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01330-y · Cited by 48
Clarke, G. J. B., Skandsen, T., Zetterberg, H., Einarsen, C. E., Feyling, C., Follestad, T., Vik, A., Blennow, K., & Håberg, A. K. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.643743 · Cited by 43
Self-citationMullane, K., & Williams, M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.027 · Cited by 32
ADAMTS13 maintains cerebrovascular integrity to ameliorate Alzheimer-like pathology
Cao, Y., Xu, H., Zhu, Y., Shi, M.-J., Wei, L., Zhang, J., Cheng, S., Shi, Y., Tong, H., Kang, L., et al. (2019) · PLOS Biology · doi:10.1371/journal.pbio.3000313 · Cited by 31
RetractedKatsumata, Y., Nelson, P. T., Estus, S., & Fardo, D. W. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2018.10.017 · Cited by 30
Lymphatic Capillaries in Aging
Jakic, B., Kerjaschki, D., & Wick, G. (2020) · Gerontology · doi:10.1159/000508459 · Cited by 28
Guha, S., Paidi, R. K., Goswami, S., Saha, P., & Biswas, S. C. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.11.021 · Cited by 26
Reduced Cardiovascular Functions in Patients with Alzheimer’s Disease
Jin, W.-S., Bu, X.-L., Wang, Y.-R., Li, L., Li, W.-W., Liu, Y.-H., Zhu, C., Yao, X.-Q., Chen, Y., Gao, C.-Y., et al. (2017) · Journal of Alzheimer's Disease · doi:10.3233/jad-170088 · Cited by 27
Tau Oligomers in Sera of Patients with Alzheimer’s Disease and Aged Controls
Kolarova, M., Sengupta, U., Bartos, A., Ricny, J., & Kayed, R. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170048 · Cited by 27
Versatile nanomaterials for Alzheimer’s disease: Pathogenesis inspired disease-modifying therapy
Xi, Y., Chen, Y., Jin, Y., Han, G., Song, M., Song, T., Shi, Y., Tao, L., Huang, Z., Zhou, J., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.02.034 · Cited by 27
Yang, C.-N., Wu, M.-F., Liu, C.-C., Jung, W.-H., Chang, Y.-C., Lee, W.-P., Shiao, Y.-J., Wu, C.-L., Liou, H.-H., Lin, S.-K., et al. (2017) · Human Molecular Genetics · doi:10.1093/hmg/ddx278 · Cited by 27
Potential importance of B cells in aging and aging-associated neurodegenerative diseases
Biragyn, A., Aliseychik, M., & Rogaev, E. (2017) · Seminars in Immunopathology · doi:10.1007/s00281-016-0615-8 · Cited by 25
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
Effect of C-phycocyanin on HDAC3 and miRNA-335 in Alzheimer’s disease
Li, Z., Gan, L., Yan, S., Yan, Y., & Huang, W. (2020) · Translational Neuroscience · doi:10.1515/tnsci-2020-0101 · Cited by 23
RetractedEvidence of beta amyloid independent small vessel disease in familial Alzheimer's disease
Littau, J. L., Velilla, L., Hase, Y., Villalba‐Moreno, N. D., Hagel, C., Drexler, D., Osorio Restrepo, S., Villegas, A., Lopera, F., Vargas, S., et al. (2022) · Brain Pathology · doi:10.1111/bpa.13097 · Cited by 20
Alzheimer’s Disease: Dawn of a New Era?
Amirrad, F., Bousoik, E., Shamloo, K., Al-Shiyab, H., Nguyen, V.-H. V., & Montazeri Aliabadi, H. (2017) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.18433/j3vs8p · Cited by 21
“This mechanism is illustrated in Figure 2 (reproduced from (26)).”
BackgroundDo Microglia default on network maintenance in Alzheimer's disease?
Southam, K. A., Vincent, A. J., & Small, D. H. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151075 · Cited by 20
GJ-4 alleviates Aβ25-35-induced memory dysfunction in mice through protecting the neurovascular unit
Zhang, Z., Liu, H., Zhao, Z., Zang, C., Ju, C., Li, F., Wang, L., Yang, H., Bao, X., Yu, Y., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110131 · Cited by 19
Zhang, Q., Song, Q., Gu, X., Zheng, M., Wang, A., Jiang, G., Huang, M., Chen, H., Qiu, Y., Bo, B., et al. (2021) · Advanced Science · doi:10.1002/advs.202001918 · Cited by 19
Mazura, A. D., & Pietrzik, C. U. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15041268 · Cited by 9
Sifting through a failed Alzheimer trial: What biomarkers tell us about what happened
Knopman, D. S. (2018) · Neurology · doi:10.1212/wnl.0000000000005073 · Cited by 5
Miao, J., Wang, J., Zhou, W., & Guo, J. (2026) · Scientific Reports · doi:10.1038/s41598-026-46671-y · Cited by 1
“By enhancing BBB-mediated efflux rather than directly binding parenchymal Aβ, PCSK9 inhibition may theoretically circumvent the risk of ARIA while providing a complementary disease-modifying mechanism 14,45 .”
Metadata
- Authors
- Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., Axel, L., Rusinek, H., Nicholson, C., Zlokovic, B. V., Frangione, B., Blennow, K., Ménard, J., Zetterberg, H., Wisniewski, T., & de Leon, M. J.
- Affiliations
- New York University (US)
- Southampton General Hospital (GB)
- NYU Langone Health (US)
- University of Gothenburg (SE)
- Université Paris Descartes (FR)
- ORCID
- Venue
- Nature Reviews Neurology
- Published
- 2015-07-21
- Volume
- 11
- Issue
- 8
- Pages
- 457-470
- ISSN
- 1759-4758 (ISSN-L)
- 1759-4766
- PMC
- PMC4694579
- OpenAlex
- W1767010801
- Cited by
- 1,678
- References
- 216
- Citations by year
- 2026: 165 · 2025: 178 · 2024: 190 · 2023: 163 · 2022: 184 · 2021: 183 · 2020: 162 · 2019: 137 · 2018: 118 · 2017: 129 · 2016: 53 · 2015: 15
- FWCI
- 12.83
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-03-29)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Reviews Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute on Aging (AG008051, AG022374, R01AG022374, AG20245, AG 12101, R01AG012101, P30AG008051, R01AG020245, R01AG013616, AG 13616)
- National Heart, Lung, and Blood Institute (HL118624, R01HL118624, HL111724, R01HL111724)
- National Institute of Neurological Disorders and Stroke (NS028642, R01NS028642)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta clearance, glymphatic system, meningeal lymphatic vessels, blood-brain barrier, astrocytes, tau hyperphosphorylation, amyloid plaques, brain waste clearance
- MeSH terms
- Alzheimer Disease, Blood-Brain Barrier, Brain, Cerebrospinal Fluid Proteins, Humans, Lymphatic System, Risk Factors, Biomarkers, Amyloid beta-Peptides, tau Proteins, Extracellular Fluid, Proteolysis, Absorption, Physiological
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
