The DOI matches its Crossref record; 131 of the 132 references it cites were found in a registry or an index.
Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis
Abstract
The amyloid cascade hypothesis of Alzheimer's disease (AD) is testable: it implies that interference with Abeta aggregation and plaque formation may be therapeutically useful. Abeta42 immunisation of amyloid precursor protein (APP) transgenic mice prevented plaque formation and caused removal of existing plaques. The first clinical studies of Abeta immunisation in AD patients (AN1792, Elan Pharmaceuticals) were halted when some patients suffered side effects. Since our confirmation that Abeta immunisation can prompt plaque removal in human AD, we have performed a clinical and neuropathological follow up of AD patients in the initial Elan Abeta immunisation trial. In immunised AD patients, we found: a lower Abeta load, with evidence that plaques had been removed; a reduced tau load in neuronal processes, but not in cell bodies; and no evidence of a beneficial effect on synapses. There were pathological "side effects" including: increased microglial activation; increased cerebral amyloid angiopathy; and there is some evidence for increased soluble/oligomeric Abeta. A pathophysiological mechanism involving effects on the cerebral vasculature is proposed for the clinical side effects observed with some active and passive vaccine protocols. Our current knowledge of the effects of Abeta immunotherapy is based on functional information from the early clinical trials and a few post mortem cases. Several further clinical studies are underway using a variety of protocols and important clinical, imaging and neuropathological data will become available in the near future. The information obtained will be important in helping to understand the pathogenesis not only of AD but also of other neurodegenerative disorders associated with protein aggregation.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“There is also evidence that amyloid removal is faster in those patients with high baseline levels, further confounding a direct comparison of anti-Aβ antibodies 90 .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“In one human study, a vaccine to Aβ did reduce plaque burden, a remarkable technical achievement [248, 249].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [248]
In the citing paper
“In the first active immunization trial, the AN-1792 vaccine seemed to show some ability to clear Aβ plaque-associated tau lesions through plaque removal179–181”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [180]
In the citing paper
“There are multiple reasons why these trials may have failed, including the late timing of the therapy. Thus, conclusions drawn from these trials may be premature (72, 73).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [72]
Citations
Cites
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975) · Journal of Psychiatric Research · doi:10.1016/0022-3956(75)90026-6 · Cited by 88,282
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
Inflammation and Alzheimer’s disease
Akiyama, H. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00124-x · Cited by 4,514
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991) · Annals of Neurology · doi:10.1002/ana.410300410 · Cited by 4,397
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002) · Nature · doi:10.1038/416535a · Cited by 4,291
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse
Schenk, D., Barbour, R., Dunn, W., Gordon, G., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., Khan, K., et al. (1999) · Nature · doi:10.1038/22124 · Cited by 3,160
Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
Hardy, J., & Allsop, D. (1991) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(91)90609-v · Cited by 2,538
Research works printed but not linked: 1
- Oh JY, Nam YJ, Jo A et al (2010) Apolipoprotein (APOE) mRNA is transported to dendrites and may have a role in synaptic structural plasticity. J Neurochem [Epub ahead of print] 2010 April 28. doi: 10.1111/j.1471-4159.2010.06773 · DOI
Cited by
Sorted by citations
The neuropathological diagnosis of Alzheimer's disease
DeTure, M. A., & Dickson, D. W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0333-5 · Cited by 3,329
“Interestingly, immunization strategies targeting Aβ peptides may be useful in alleviating amyloid plaque burden, while shifting amyloid into CAA, sometimes associated with inflammation and hemorrhage [51, 52].”
BackgroundNelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050
Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease
Prinz, M., & Priller, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3722 · Cited by 1,329
Microglial priming in neurodegenerative disease
Perry, V. H., & Holmes, C. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.38 · Cited by 1,127
Self-citationTau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113
Cerebral 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
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786
The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics
Karran, E., & De Strooper, B. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00391-w · Cited by 742
“There does not appear to be a correlation between rate of amyloid removal and the incidence of ARIA-E, in contrast to what has previously been postulated 91 and as we will discuss below.”
Sperling, R., Salloway, S., Brooks, D. J., Tampieri, D., Barakos, J., Fox, N. C., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., et al. (2012) · The Lancet Neurology · doi:10.1016/s1474-4422(12)70015-7 · Cited by 512
Alzheimer disease therapy—moving from amyloid-β to tau
Giacobini, E., & Gold, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2013.223 · Cited by 501
Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease
de la Monte, S. M. (2012) · Current Alzheimer Research · doi:10.2174/156720512799015037 · Cited by 468
“proinflammatory responses with increased microglial activation, cerebral amyloid angiopathy, and accumulation of soluble neurotoxic oligomeric A PP-A [271], may have adversely influenced the clinical course of AD.”
BackgroundAnimal Models of Alzheimer Disease
LaFerla, F. M., & Green, K. N. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006320 · Cited by 419
“Immunotherapy has progressed into numerous clinical trials and has been shown to reduce both Ab and tau levels in patients (Boche et al. 2010), as shown in mouse models (Schenk et al. 1999; Oddo et al. 2004).”
BackgroundAmyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics
Hampel, H., Elhage, A., Cho, M., Apostolova, L. G., Nicoll, J. A. R., & Atri, A. (2023) · Brain · doi:10.1093/brain/awad188 · Cited by 412
“45 Poorly understood mechanistic aspects include whether A β is transported to the vasculature in association with antibody (i.e. in the form of immune complexes) as a conjugate to apoli-poprotein E (APOE) or as unassociated soluble A β .”
BackgroundSelf-citationReview: sporadic cerebral amyloid angiopathy
Attems, J., Jellinger, K., Thal, D. R., & Van Nostrand, W. (2011) · Neuropathology and Applied Neurobiology · doi:10.1111/j.1365-2990.2010.01137.x · Cited by 371
Nelson, P. T., Head, E., Schmitt, F. A., Davis, P. R., Neltner, J. H., Jicha, G. A., Abner, E. L., Smith, C. D., Van Eldik, L. J., Kryscio, R. J., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0826-y · Cited by 365
“However, the limitations of the conclusions that can be drawn from the few autopsied anti-Ab immunotherapy cases have been acknowledged [34] and in fact some beneficial effects of the human immunotherapy studies have been seen in clinical trials [31, 35, 191, 202].”
Cognitive symptoms of Alzheimer’s disease: clinical management and prevention
Joe, E., & Ringman, J. M. (2019) · BMJ · doi:10.1136/bmj.l6217 · Cited by 339
Mao, P., & Reddy, P. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.005 · Cited by 316
“Based on these fundamental observations, immunization of AD patients with synthetic full length Aβ42 (AN1792, Elan Pharmaceuticals) has been studied in a randomized, doubleblind, placebo-controlled phase 2a clinical trial [70,71].”
Immunotherapy Targeting Pathological Tau Prevents Cognitive Decline in a New Tangle Mouse Model
Boutajangout, A., Quartermain, D., & Sigurdsson, E. M. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4363-10.2010 · Cited by 272
“…trial, A plaque clearance had limited effect on tau pathology (Nicoll et al., 2003; Ferrer et al., 2004; Masliah et al., 2005a; Holmes et al., 2008; Boche et al., 2010a,b; Serrano-Pozo et al., 2010), which emphasizes the need for therapy that specifically targets this other major hallmark of the…”
BackgroundPiazza, F., Greenberg, S. M., Savoiardo, M., Gardinetti, M., Chiapparini, L., Raicher, I., Nitríni, R., Sakaguchi, H., Brioschi, M., Billo, G., et al. (2013) · Annals of Neurology · doi:10.1002/ana.23857 · Cited by 239
“Moreover, given the similarities between ARIA developing spontaneously and those observed during immunization trials, anti-Ab autoantibodies can be considered as novel potential biomarkers in future amyloid-modifying therapies for the treatment of AD and CAA.”
BackgroundEmerging Concepts in Alzheimer's Disease
Vinters, H. V. (2014) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-163927 · Cited by 244
A review on advances of treatment modalities for Alzheimer's disease
Thoe, E. S., Fauzi, A., Tang, Y.-Q., Chamyuang, S., & Chia, A. Y. Y. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119129 · Cited by 234
Nicoll, J. A. R., Buckland, G. R., Harrison, C. H., Page, A. M., Harris, S., Love, S., Neal, J., Holmes, C., & Boche, D. (2019) · Brain · doi:10.1093/brain/awz142 · Cited by 213
“The reduction in tau-containing plaque-associated dystrophic neurites is a striking consequence of immunization-mediated removal of amyloid-b from the cortex and has been described previously (Nicoll et al., 2003; Ferrer et al., 2004; Boche et al., 2010b).”
BackgroundResultInfluentialSelf-citationCongdon, E. E., Gu, J., Sait, H. B. R., & Sigurdsson, E. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.491001 · Cited by 195
“Although immunizationwas effective at reducing amyloid burden, there was no beneficial effect on synapses or clinical progression (8).”
BackgroundAPOE-ε2 and APOE-ε4 Correlate With Increased Amyloid Accumulation in Cerebral Vasculature
Nelson, P. T., Pious, N. M., Jicha, G. A., Wilcock, D. M., Fardo, D. W., Estus, S., & Rebeck, G. W. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31829a25b9 · Cited by 150
Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders?
Bayer, T. A. (2013) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2013.03.007 · Cited by 149
The transcription factor PU.1 is critical for viability and function of human brain microglia
Smith, A. M., Gibbons, H. M., Oldfield, R. L., Bergin, P. M., Mee, E. W., Faull, R. L. M., & Dragunow, M. (2013) · Glia · doi:10.1002/glia.22486 · Cited by 141
“In Alzheimer’s disease microglia may be helpful in clearing the brain of extracellular Ab42 deposits (Bard et al., 2000; Boche et al., 2010; Rogers et al., 2002).”
BackgroundThe endocytic pathway in microglia during health, aging and Alzheimer’s disease
Solé-Domènech, S., Cruz, D. L., Capetillo-Zarate, E., & Maxfield, F. R. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.07.002 · Cited by 133
BACE inhibition-dependent repair of Alzheimer’s pathophysiology
Keskin, A. D., Kekuš, M., Adelsberger, H., Neumann, U., Shimshek, D. R., Song, B., Zott, B., Peng, T., Förstl, H., Staufenbiel, M., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1708106114 · Cited by 125
Wang, A., Das, P., Switzer, R. C., Golde, T. E., & Jankowsky, J. L. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5077-10.2011 · Cited by 118
“Admittedly, one conundrum in this interpretation is the appearance in several immunized patients of cortical patches lacking amyloid immediately adjacent to areas with considerable plaque accumulation (Nicoll et al., 2003; Boche et al., 2010).”
BackgroundPasquier, F., Sadowsky, C., Holstein, A. R., Prince, G. L., Peng, Y., Jackson, N. M., Fox, N. C., Ketter, N., Liu, E., Ryan, J. M., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150376 · Cited by 108
Ryan, P., Patel, B., Makwana, V., Jadhav, H. R., Kiefel, M. J., Davey, A. K., Reekie, T. A., Rudrawar, S., & Kassiou, M. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00185 · Cited by 101
Using Pittsburgh Compound B for In Vivo PET Imaging of Fibrillar Amyloid-Beta
Cohen, A. D., Rabinovici, G. D., Mathis, C. A., Jagust, W. J., Klunk, W. E., & Ikonomović, M. D. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-394816-8.00002-7 · Cited by 103
“While Aβ immunization appears to be effective in reducing amyloid pathology in AD patients, this intervention has been observed to activate microglia reaction in the brain and it can result in severe side effects (Boche et al., 2010).”
Li, X., & Buxbaum, J. N. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-79 · Cited by 104
“Nonetheless the hypothesis remains dominant with the failures being interpreted as being related to either inadequate specificity (in the case of g-secretase inhibitors, resulting in off-target toxicity), unresponsive stage of disease, or neurovascular inflammation (as with the anti-Ab antibodies) [144].”
BackgroundBridges, L., Andoh, J., Lawrence, A. J., Khoong, C. H. L., Poon, W. W., Esiri, M. M., Markus, H. S., & Hainsworth, A. H. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000124 · Cited by 98
“Brain uptake of IgG and other macromolecules may occur transcellularly or via ‘‘leaky’’ tight junctions (50, 51).”
Blood–brain barrier leakage and perivascular inflammation in cerebral amyloid angiopathy
Kozberg, M. G., Yi, I., Freeze, W. M., Auger, C. A., Scherlek, A. A., Greenberg, S. M., & van Veluw, S. J. (2022) · Brain Communications · doi:10.1093/braincomms/fcac245 · Cited by 94
“These episodes are termed CAA-related inflammation (CAA-ri).7–9 In these cases, regions of inflammation have an increased CMB burden, suggesting that active inflammation may contribute to haemorrhage.10 Additionally, Pittsburgh compound B positron emission tomography imaging studies suggest that CAA-ri may involve Aβ…”
BackgroundXu, R., Wang, J., Xu, J., Song, X., Huang, H., Feng, Y., & Fu, C. (2020) · International Journal of Nanomedicine · doi:10.2147/ijn.s236922 · Cited by 88
Amyloid-related imaging abnormalities: manifestations, metrics and mechanisms
Greenberg, S. M., Bax, F., & van Veluw, S. J. (2025) · Nature Reviews Neurology · doi:10.1038/s41582-024-01053-8 · Cited by 107
Ryan, P., Xu, M., Davey, A. K., Danon, J. J., Mellick, G. D., Kassiou, M., & Rudrawar, S. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00143 · Cited by 84
Moore, K. B. E., Hung, T.-J., & Fortin, J. S. (2023) · Drug Discovery Today · doi:10.1016/j.drudis.2023.103487 · Cited by 93
Shahaduzzaman, M., Nash, K. R., Hudson, C., Masroor, S., Grimmig, B. A., Lin, X., Bai, G., Liu, H., Ugen, K. E., Cao, C., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116841 · Cited by 88
Vasilevko, V., Passos, G. F., Quiring, D., Head, E., Kim, R. C., Fisher, M., & Cribbs, D. H. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05786.x · Cited by 74
“In addition, both active and passive immunotherapy increase the risk of adverse cerebral vascular events, including increased densities of cortical microhemorrhages and microvascular lesions, white matter abnormalities and vasogenic edema [103,108–112].”
BackgroundInnate Immunity in Alzheimer’s Disease: A Complex Affair
Guillot‐Sestier, M., & Town, T. (2013) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527311312050008 · Cited by 72
Aβ immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy
Sakai, K., Boche, D., Carare, R., Johnston, D., Holmes, C., Love, S., & Nicoll, J. A. R. (2014) · Acta Neuropathologica · doi:10.1007/s00401-014-1340-9 · Cited by 72
“However, as the exacerbation of concentric splitting after immunization occurs in the context of enhanced mobilization of plaque Aβ and its eventual perivascular clearance [4, 6, 31], we suggest that the ‘splitting’ may result from enhanced initial deposition of Aβ-apoE in the tunica media, associated with destruction…”
Self-citationAnimal models of cerebral amyloid angiopathy
Jäkel, L., Nostrand, W. E. V., Nicoll, J. A. R., Werring, D. J., & Verbeek, M. M. (2017) · Clinical Science · doi:10.1042/cs20170033 · Cited by 71
“clinical trials seem likely to be due largely to these changes in CAA (196, 197).”
BackgroundSelf-citationKile, S. J., Au, W. J., Parise, C. A., Rose, K., Donnel, T., Hankins, A. I., Chan, M., & Ghassemi, A. (2015) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2015-311486 · Cited by 68
Immunotherapies for Alzheimer’s Disease—A Review
Valiukas, Z., Ephraim, R., Tangalakis, K., Davidson, M., Apostolopoulos, V., & Feehan, J. (2022) · Vaccines · doi:10.3390/vaccines10091527 · Cited by 70
“The exact mechanism of this was unknown and determined to have no clear relation to serum anti-Aβ42 antibody titers but may have been an autoimmune response rising from T cell interactions [85,86].”
BackgroundHerring, A., Lewejohann, L., Panzer, A.-L., Donath, A., Kröll, O., Sachser, N., Paulus, W., & Keyvani, K. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.03.007 · Cited by 63
Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer's disease
Ameen‐Ali, K. E., Wharton, S. B., Simpson, J. E., Heath, P. R., Sharp, P. S., & Berwick, J. (2017) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12440 · Cited by 59
Ajit, D., Woods, L. T., Camden, J. M., Thebeau, C. N., El-Sayed, F. G., Greeson, G. W., Erb, L., Petris, M. J., Miller, D. C., Sun, G. Y., et al. (2013) · Molecular Neurobiology · doi:10.1007/s12035-013-8577-5 · Cited by 60
“plaque load and increase microglial cell accumulation [33, 71–73].”
BackgroundTakata, K., Takada, T., Ito, A., Asai, M., Tawa, M., Saito, Y., Ashihara, E., Tomimoto, H., Kitamura, Y., & Shimohama, S. (2012) · International Journal of Alzheimer s Disease · doi:10.1155/2012/685739 · Cited by 60
“Reports on AD patients treated with Aβ immunization also indicate microglial contribution to Aβ clearance in human AD brains [42, 43].”
Backgroundp-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice
Walls, K. C., Ager, R. R., Vasilevko, V., Cheng, D., Medeiros, R., & LaFerla, F. M. (2014) · Neuroscience Letters · doi:10.1016/j.neulet.2014.05.047 · Cited by 62
Antibody-based therapy in Alzheimer's disease
Pul, R., Dodel, R. C., & Stangel, M. (2011) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2011.552884 · Cited by 59
“Follow-up analyses of AD patients in the AN1792 trial revealed a reduced tau load in neuronal processes but not in the neuronal cell bodies [169].”
BackgroundAlzheimer disease neuropathology in a patient previously treated with aducanumab
Plowey, E. D., Bussière, T., Rajagovindan, R., Sebalusky, J., Hamann, S., von Hehn, C., Castrillo‐Viguera, C., Sandrock, A. W., Haeberlein, S. B., van Dyck, C. H., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02433-4 · Cited by 60
Therapeutic targets of brain insulin resistance in sporadic Alzheimer s disease
de la Monte, S. M. (2012) · Frontiers in Bioscience-Elite · doi:10.2741/e482 · Cited by 57
tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-β
Park, L., Zhou, J., Koizumi, K., Wang, G., Anfray, A., Ahn, S. J., Seo, J., Zhou, P., Zhao, L., Paul, S. M., et al. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.1140-20.2020 · Cited by 59
“…be beneficial in amyloidrelated imaging abnormalities, an adverse effect of anti-Ab immunotherapy (Sperling, 2011) characterized by perivascular inflammation, microhemorrhages, and edema attributed to the vascular effects of Ab released from amyloid plaques (Boche et al., 2010; Sakai et al., 2014).”
BackgroundMancini, S., Minniti, S., Gregori, M., Sancini, G., Cagnotto, A., Couraud, P., Ordóñez‐Gutiérrez, L., Wandosell, F. G., Salmona, M., & Re, F. (2015) · Nanomedicine Nanotechnology Biology and Medicine · doi:10.1016/j.nano.2015.09.003 · Cited by 54
Nanomedicine in Alzheimer's disease: Amyloid beta targeting strategy
Tosi, G., Pederzoli, F., Belletti, D., Vandelli, M. A., Forni, F., Duskey, J. T., & Ruozi, B. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.03.001 · Cited by 53
Alzheimer's Therapeutics: Translation of Preclinical Science to Clinical Drug Development
Savonenko, A. V., Melnikova, T., Hiatt, A., Li, T., Worley, P. F., Troncoso, J. C., Wong, P. C., & Price, D. L. (2011) · Neuropsychopharmacology · doi:10.1038/npp.2011.211 · Cited by 52
“The most recent update on the neuropathology in cases from the original Phase I trial reports significant removal of Ab plaques and plaque-associated tau-positive dystrophic neurites but no differences between immunized and control AD cases in the density of phospho-tau-positive neuronal bodies (a marker for Braak Sta…”
BackgroundInfluentialPatterns of cerebral amyloid angiopathy define histopathological phenotypes in A lzheimer's disease
Allen, N., Robinson, A., Snowden, J. S., Davidson, Y. S., & Mann, D. M. A. (2013) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12070 · Cited by 49
Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease
Suzanne, M. (2011) · Frontiers in Bioscience-Elite · doi:10.2741/482 · Cited by 50
Immunotherapy targeting pyroglutamate-3 Aβ: prospects and challenges
Cynis, H., Frost, J. L., Crehan, H., & Lemere, C. A. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0115-2 · Cited by 49
Endothelin receptor antagonists: Potential in Alzheimer's disease
Palmer, J. C., & Love, S. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2010.12.008 · Cited by 49
Davtyan, H., Zagorski, K., Rajapaksha, H., Hovakimyan, A., Davtyan, A., Petrushina, I., Kazarian, K., Cribbs, D. H., Petrovsky, N., Agadjanyan, M. G., et al. (2016) · Scientific Reports · doi:10.1038/srep28912 · Cited by 47
Feng, L., Long, H., Liu, R.-K., Sun, D., Liu, C., Long, L., Li, Y., Chen, S., & Xiao, B. (2013) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-013-9943-6 · Cited by 45
Recent developments with tau-based drug discovery
Iqbal, K., Liu, F., & Gong, C. (2018) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2018.1445084 · Cited by 46
“was, in fact, found to be effective in clearing the brain of the amyloid plaques but not neurofibrillary tangles [18].”
BackgroundP2Y receptors in Alzheimer's disease
Erb, L., Chen, C., Ajit, D., & Weisman, G. A. (2014) · Biology of the Cell · doi:10.1111/boc.201400043 · Cited by 45
“The crucial role of microglia in controlling Aβ levels has been demonstrated in AD mouse models and AD patients where Aβ immunisation has been shown to decrease plaque load and increase microglial cell accumulation (Schenk et al., 1999; Nicoll et al., 2003; Boche et al., 2010).”
BackgroundBastard, N. L., Aerts, L., Sleegers, K., Martin, J., Broeckhoven, C. V., Deyn, P. P. D., & Engelborghs, S. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-110029 · Cited by 41
Boche, D., & Nicoll, J. A. R. (2020) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12642 · Cited by 41
Self-citationDantrolene, A Treatment for Alzheimer Disease?
Li, L., & Wei, H. (2014) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000076 · Cited by 40
Nanoliposomes as a Therapeutic Tool for Alzheimer’s Disease
Ordóñez‐Gutiérrez, L., & Wandosell, F. G. (2020) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2020.00020 · Cited by 40
“A complementary phase II trial was initiated in 2001, however, 6% of the immunized patients presented symptoms of aseptic meningoencephalitis, and the trial was terminated early in 2002 (Wisniewski and Frangione, 2005; Boche et al., 2010).”
BackgroundInvestigating Interventions in Alzheimer's Disease with Computer Simulation Models
Proctor, C. J., Boche, D., Gray, D. A., & Nicoll, J. A. R. (2013) · PLoS ONE · doi:10.1371/journal.pone.0073631 · Cited by 38
“This intervention also predicts slightly lower levels of phospho-tau (compare green curves in Figure 2A and 2F) in agreement with neuropathological data [10].”
InfluentialSelf-citationCrane, A., Brubaker, W. D., Johansson, J. U., Trigunaite, A., Ceballos, J., Bradt, B. M., Glavis‐Bloom, C., Wallace, T. L., Tenner, A. J., & Rogers, J. (2017) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2017.04.015 · Cited by 34
“Although, as noted, these findings do not disallow CNS actions of Ab immunotherapy, they do strongly suggest that peripheral effects should be considered as well—particularly because peripheral strategies might avoid the CNS adverse effects that have been encountered in previous AD immunotherapy trials [1,4,5].”
BackgroundRoher, A. E., Cribbs, D. H., Kim, R. C., Maarouf, C. L., Whiteside, C. M., Kokjohn, T. A., Daugs, I. D., Head, E., Liebsack, C., Serrano, G. E., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0059735 · Cited by 34
Therapeutic Targeting of the Endoplasmic Reticulum in Alzheimers Disease
Chadwick, W., Mitchell, N. A., Martin, B., & Maudsley, S. R. (2012) · Current Alzheimer Research · doi:10.2174/156720512799015055 · Cited by 34
“Over the past decade several therapeutic strategies, borne out of the amyloidogenic hypothesis of Alzheimer’s, have been developed that directly address Aβ aggregation [5], production [6] or clearance [7].”
BackgroundTobinick, E. L. (2012) · Current Alzheimer Research · doi:10.2174/156720512799015073 · Cited by 34
“edu treatment groups, including brain inflammation 1 , worsening cognition, or excess mortality [8,13-18].”
BackgroundAβ43 in human Alzheimer’s disease: effects of active Aβ42 immunization
Jäkel, L., Boche, D., Nicoll, J. A. R., & Verbeek, M. M. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0791-6 · Cited by 29
“Although this is a widely accepted method for relative protein quantification [6, 29, 30], a possible limitation of our study is that comparison of antigen load stained by different antibodies is not fully possible.”
MethodSelf-citationFroestl, W., Pfeifer, A., & Muhs, A. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121729 · Cited by 27
“The scientific harvest of this single clinical trial is listed in chronological order [1254–1286] (Thomson Reuters Pharma, update of August 24, 2012).”
BackgroundBouter, Y., Liekefeld, H., Pichlo, S., Westhoff, A. C., Fenn, L., Bakrania, P., & Bayer, T. A. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02418-3 · Cited by 26
Darreh‐Shori, T., Hosseini, S. M., & Nordberg, A. K. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-130845 · Cited by 23
“This may strongly deplete extrasynaptic ACh levels and disturb the proper functional status of cholinoceptives microglia and/or astrocytes, endothelial, and smooth muscle cells comprising the main component of micro-blood vessels in the brain [75, 76].”
Bazan, N. G., Halabi, A., Ertel, M. K., & Petasis, N. A. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-374947-5.00034-1 · Cited by 23
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
“Phospho-tau analysis showed a reduction of aggregated tau in neuronal processes (44).”
BackgroundRoher, A. E., Maarouf, C. L., & Kokjohn, T. A. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-150757 · Cited by 22
“In the AN-1792 clinical trials, neuropathology and neurochemical analyses hinted that the anti-A antibodies reached their targets [81–87].”
BackgroundPerspectives on the Tertiary Prevention Strategy for Alzheimer's Disease
Bu, X., Jiao, S., Lian, Y., & Wang, Y. (2015) · Current Alzheimer Research · doi:10.2174/1567205013666151215110114 · Cited by 20
“The first active Aβ vaccine AN1792 lowered brain Aβ plaques, but did not provide benefits in synaptic integrity or cognitive performance [11].”
BackgroundHarnessing the Immune System for Treatment and Detection of Tau Pathology
Congdon, E. E., Krishnaswamy, S., & Sigurdsson, E. M. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132435 · Cited by 20
“In a Phase II Bapineuzumab trial, significant decrease in phospho-tau was detected in treated individuals [10, 21].”
Scherlek, A. A., Kozberg, M. G., Nicoll, J. A. R., Perosa, V., Freeze, W. M., van der Weerd, L., Bacskai, B. J., Greenberg, S. M., Frosch, M. P., Boche, D., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac021 · Cited by 20
“This observation is detected with the addition of cases with longer post-immunization survival times and thus could reflect that the response to ongoing neurodegenerative processes, such as tau pathology, is still progressing.(3,13) Future studies are needed to determine the nature of these neuroinflammatory responses.”
Self-citationAMBAR, an Encouraging Alzheimer's Trial That Raises Questions
Loeffler, D. A. (2020) · Frontiers in Neurology · doi:10.3389/fneur.2020.00459 · Cited by 20
Alzheimer Disease and Cellular Mechanisms of Memory Storage
Arshavsky, Y. I. (2014) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0000000000000043 · Cited by 19
“Unfortunately, these trials did not yield anticipated positive results (32, 33).”
BackgroundHunter, J. M., Bowers, W. J., Maarouf, C. L., Mastrangelo, M. A., Daugs, I. D., Kokjohn, T. A., Kalback, W. M., Luehrs, D. C., Valla, J., Beach, T. G., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-110608 · Cited by 18
Leclerc, B., & Abulrob, A. (2013) · The Scientific World JOURNAL · doi:10.1155/2013/589308 · Cited by 18
Venkataramani, V., Wirths, O., Budka, H., Härtig, W., Kovács, G. G., & Bayer, T. A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111379 · Cited by 17
“Therefore passive immunization has become a valuable alternative [44, 45].”
Bosch, M. N., Gimeno‐Bayón, J., Rodríguez, M. J., Pugliese, M., & Mahy, N. (2013) · Current Alzheimer Research · doi:10.2174/15672050113109990129 · Cited by 17
“impairments [7–9], and the same was observed in human beings [10].”
BackgroundTatiparti, K., Sau, S., Rauf, M. A., & Iyer, A. K. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.09.025 · Cited by 16
Liu, Z., Chen, H., Li, T., Xu, L., & Du, H. (2012) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12028 · Cited by 16
Alzheimer’s disease and immunotherapy: what is wrong with clinical trials?
Matsumoto, Y., & Kohyama, K. (2015) · ImmunoTargets and Therapy · doi:10.2147/itt.s49923 · Cited by 12
Combined treatment of Aβ immunization with statin in a mouse model of Alzheimer's disease
Kou, J., Song, M., Pattanayak, A., Lim, J. E., Yang, J., Cao, D., Li, L., & Fukuchi, K. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.01.008 · Cited by 12
“…Aβ to blood vessels based on one of the postulated mechanisms for amyloid plaque clearance by Aβ immunotherapy, which states that anti-Aβ antibodies directly interact with amyloid plaques, resulting in disaggregation and solubilization of Aβ fibrils (Bacskai et al., 2002; Boche et al., 2010).”
Effects of Microglial Cytokines on Alzheimer’s Disease-Related Phenomena
Ji, Y., Wang, X., Kalicki, C. H., Menta, B. W., Baumgardner, M., Koppel, S. J., Weidling, I. W., Ortiz, J. P., Wilkins, H., & Swerdlow, R. H. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-180820 · Cited by 12
Chauhan, N. B., Davis, F., & Xiao, C. (2011) · Vaccine · doi:10.1016/j.vaccine.2011.08.009 · Cited by 13
Nemirovsky, A., Shapiro, J., Baron, R., Kompaniets, A., & Monsonego, A. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.03.017 · Cited by 10
“Indeed, although a clear correlation between the level of antibody production and the extent of plaque clearance was obtained in the Elan AN-1792 clinical trial, some cases demonstrated no profound plaque clearance regardless of Aβ antibody production (Boche et al., 2010), suggesting that either Aβ antibody titers wer…”
InfluentialYang, P. C., Guo, Y., Sun, Y., Yu, B., Zhang, H., Wu, J., Yu, X., Wu, H., & Kong, W. (2019) · BMC Immunology · doi:10.1186/s12865-019-0289-9 · Cited by 9
Pyun, J.-M., Kang, M. J., Baek, S. J., Lee, K. S., Park, Y. H., & Kim, S. (2024) · The Journal of Prevention of Alzheimer s Disease · doi:10.14283/jpad.2024.49 · Cited by 8
“…behind ARIA is suspected to involve the antibody-mediated breakdown of neuritic plaques, resulting in the release of Aβ and its deposition within vessels; this leads to CAA, perivascular inflammation, and compromised Aβ clearance (3), thereby indicating a potential connection between CAA and ARIA.”
Metadata
- Authors
- Boche, D., Denham, N., Holmes, C., & Nicoll, J. A. R.
- Affiliations
- Southampton General Hospital (GB)
- Corresponding author
- Boche, Delphine
- Venue
- Acta Neuropathologica
- Published
- 2010-07-15
- Volume
- 120
- Issue
- 3
- Pages
- 369-384
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2077023014
- Cited by
- 135
- References
- 132
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 1 · 2023: 3 · 2022: 8 · 2021: 1 · 2020: 8 · 2019: 12 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 5 · 2014: 15 · 2013: 19 · 2012: 15
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta immunotherapy, amyloid-beta 42, amyloid hypothesis, amyloid plaques, tau pathology, microglial activation, cerebral amyloid angiopathy, cerebral vasculature, vaccine side effects, amyloid precursor protein transgenic mice, Alzheimer's disease pathogenesis
- MeSH terms
- Alzheimer Disease, Animals, Brain, Clinical Trials as Topic, Humans, Peptide Fragments, Amyloid beta-Peptides, Immunotherapy, Active, Alzheimer Vaccines, Mice
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
