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Long-term effects of Aβ42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial
Abstract
Background Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes.Methods In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Abeta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Abeta immunostaining (Abeta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model.Findings 20 participants--15 in the AN1792 group, five in the placebo group--died before follow-up started. A further 22 patients--19 in the AN1792 group, three in the placebo group--died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Abeta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in Abeta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group.Interpretation Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.
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“A study involving cognitively healthy adults showed that Aβ in CSF or the hippocampus increases after sleep deprivation or slow-wave sleep disruption, which indicates the complexity of Aβ kinetics [59, 60, 61].”
From Clinical trials of new drugs for Alzheimer disease (2020) · cites this paper as [61]
In the citing paper
“Several anti-Aβ therapeutic strategies are being pursued to treat AD; however, it is likely that treatment will need to begin during the preclinical phase to prevent or limit plaque accumulation to be beneficial in reducing the risk of developing AD (51, 52).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [51]
In the citing paper
“Recent clinical trials attempting to replicate the benefits of Aβ immunotherapy seen in mouse models have been primarily unsuccessful in preventing early cognitive decline in AD patients despite significantly decreasing the amyloid burden”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Holmes et al., 2008
In the citing paper
“While safety concerns caused this trial to terminate prematurely, subsequent clinical analyses were at best unimpressive [250, 251].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [251]
In the citing paper
“There have been cases in which individuals with mid- to late-stage clinical AD were administered anti-Aβ immunotherapy that partially cleared AβPs, but this clearance did not seem to mitigate NFT formation or the inexorable disease course (69-71).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [70]
In the citing paper
“Often neglected is the question of lesion turnover (i.e. AβPs being possibly reabsorbed during life so that they would not be “counted” at autopsy), which seems to occur in some subjects (70, 270).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [70]
In the citing paper
“Aβ vaccine trials also attest to the ability of the immune system to clear diffuse AβPs (69, 70, 271), but it is not known whether toxic APP metabolites or other plaque components remain after clearance of fibrillar Aβ-peptides (73, 272).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [70]
In the citing paper
“a subset of patients from the aborted Wyeth/ELAN active Aβ vaccine trial that were studied at autopsy showed Aβ plaque removal in the absence of cognitive improvement [75].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [75]
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“• Lowering amyloid levels through immunotherapy against the amyloid caused harm to the recipients, including neuroinflammation [52].”
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BackgroundMechanisms of AD neurodegeneration may be independent of Aβ and its derivatives
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“Furthermore, recent studies in humans showed that clearance of amyloid depositions resulted neither in cognitive improvement nor in a decreased rate of mental deterioration (Holmes et al., 2008) suggesting that NPs may not be the driving force of the neurodegeneration and cognitive decline of AD.”
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“Furthermore, in the Holmes study (Holmes et al. 2008), after a six-year follow-up from phase I immunization with Ab42-AN1792 (Elan Pharmaceuticals), the evidence of plaque reduction was not associated with any delay in disease progression to either severe dementia or death.”
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“Similar to the canine immunization results, in recent human clinical trials, immunization of AD patients reduced A load but had only minor effects on cognitive improvement and did not slow disease progression (Gilman et al., 2005; Holmes et al., 2008; Kokjohn and Roher, 2009).”
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“However, although there is a sense of optimism about this, a potential concern is that bapineuzumab also partially cleared plaques, albeit in the context of amyloid-related imaging abnormalities, without evidence for clinical utility (Holmes et al. 2008).”
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“MP presence do not always correlate well with structural atrophy and/or cognitive decline levels, whereas therapeutic drugs created to reduce MP levels have demonstrated poor modulatory effects on disease progression (Holmes et al., 2008).”
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“Patients that had consented for long-term clinical follow-up, post-mortem neuropathological examination, or both, entered a phase I randomized, placebo-controlled trial of immunization with Aβ42 (AN-1792 vaccine) (Holmes et al 2008).”
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“In a follow-up study the immunised group exhibited some reduction in brain Aβ load compared to the control group but failed to improve cognitive markers in the small sample studied (Holmes et al., 2008; reviewed in St George-Hyslop and Morris, 2008).”
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Cowan, C. M., Quraishe, S., & Mudher, A. K. (2012) · Biochemical Society Transactions · doi:10.1042/bst20120135 · Cited by 62
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“Although immunization with Ab-42 resulted in enhanced clearance of amyloid plaques, this did not prevent progressive neurodegeneration and cognitive deterioration [40].”
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The role of the immune system in driving neuroinflammation
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“…follow-up studies, post-mortem examinations provided evidence of Aβ plaque clearance, whereas tau and cerebral amyloid angiopathy (CAA) pathologies did not decrease and time to onset of severe dementia was not increased (Ferrer et al., 2004; Holmes et al., 2008; Nicoll et al., 2003, 2006).”
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“Deposition of Ab in brain will harm synapse, disturb neuronal communication, and lead to neurocyte apoptosis (Holmes et al. 2008; Riviere et al. 2007; Selkoe 1997; Selkoe 1998).”
Recent Progress in the Pharmacotherapy of Alzheimer’s Disease
Khoury, R., Patel, K., Gold, J., Hinds, S., & Grossberg, G. T. (2017) · Drugs & Aging · doi:10.1007/s40266-017-0499-x · Cited by 62
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Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
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“Active immunotherapy AN-1792 (synthetic Aβ42, Janssen) ≥ 60–70% Aβ load reduction in the brain (post-mortem immonustaining) Discontinued in 2002 (mild to moderate AD patients) Meningoencephalitis (208) (209) (210) CAD106 (multiple copies of Aβ1-6 peptide, Novartis) 1.”
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“Both Aβ-×-PrPCand β-amyloidplay a key role in the evolution of disease progression, but disappearance of β-amyloid plaques via a vaccine does not mitigate neurodegeneration (Holmes et al. 2008).”
Immunization Therapy for Alzheimer Disease: A Comprehensive Review of Active Immunization Strategies
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“Such idea corresponds with current understanding of “anti-Aβ” therapies: once clinical symptoms develop, other mechanisms would be required to treat AD (Holmes et al., 2008; Burns, 2009).”
BackgroundBapineuzumab: Anti-β-Amyloid Monoclonal Antibodies for the Treatment of Alzheimer‘s Disease
Panza, F., Frisardi, V., Imbimbo, B. P., D’Onofrio, G., Pietrarossa, G., Seripa, D., Pilotto, A., & Solfrizzi, V. (2010) · Immunotherapy · doi:10.2217/imt.10.80 · Cited by 59
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“At post-mortem, there were fewer plaques in the group treated with active immunisation compared with placebo, although immunisation did not prevent the ongoing neurodegeneration or clinical progression to severe dementia [19].”
Backgroundp-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice
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Alzheimer's disease and periodontitis - an elusive link
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Antibody-based therapy in Alzheimer's disease
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“Although, there was a striking effect on Ab clearance of parenchymal plaques in the brains of autopsy cases, N-terminally directed antibodies did not seem to modify the cognitive decline in those patients [40].”
BackgroundAlzheimers Disease: Pathological Mechanisms and Recent Insights
Niedowicz, D. M., Nelson, P. T., & Murphy, M. P. (2011) · Current Neuropharmacology · doi:10.2174/157015911798376181 · Cited by 62
Curcumin improves tau-induced neuronal dysfunction of nematodes
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Alzheimer disease neuropathology in a patient previously treated with aducanumab
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Takashima, A. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1090 · Cited by 57
Pharmacotherapeutic targets in Alzheimer's disease
Biran, Y., Masters, C. L., Barnham, K. J., Bush, A. I., & Adlard, P. A. (2008) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2008.00595.x · Cited by 59
Shin, J., Lee, J. K., Lee, J. E., Min, W., Schuchman, E. H., Jin, H. K., & Bae, J. (2011) · Stem Cells · doi:10.1002/stem.659 · Cited by 56
Alzheimer's disease therapeutic research: the path forward
Aisen, P. S. S. (2009) · Alzheimer s Research & Therapy · doi:10.1186/alzrt2 · Cited by 59
A Systematic Review of Single Chinese Herbs for Alzheimer′s Disease Treatment
Fu, L., & Li, J.-T. (2009) · Evidence-based Complementary and Alternative Medicine · doi:10.1093/ecam/nep136 · Cited by 57
“In a recent clinical trial, an experimental vaccine was found to clear the amyloid plaques, but it did not have any significant effect on dementia [7], suggesting that neurofibrillary tangles could play a more important role than amyloid plaques in the pathophysiology of AD.”
BackgroundGeorge, D. R., & Whitehouse, P. J. (2011) · The Gerontologist · doi:10.1093/geront/gnr042 · Cited by 56
“Most recently, compounds such as Dimebon, Alzhemed, and Flurizan have failed to live up to the hype (Miller, 2010), while the amyloid vaccine developed by the drug company Elan did not demonstrate capacity to prevent neurodegeneration and improve cognition (Holmes et al., 2008).”
The role of β-amyloid peptide in neurodegenerative diseases
Maltsev, A. V., Bystryak, S. M., & Galzitskaya, O. V. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2011.03.002 · Cited by 57
Haller, S., Missonnier, P., Herrmann, F. R., Rodriguez, C. K., Deiber, M., Nguyen, D. D., Gold, G., Lövblad, K., & Giannakopoulos, P. (2012) · American Journal of Neuroradiology · doi:10.3174/ajnr.a3223 · Cited by 56
“However, recent studies pointed to their limited performance in patients with clinically overt dementia.(3,4) To date, the identification of patients at high risk for rapid cognitive decline is considered a prerequisite for future curative strategies in AD.”
ResultNew and emerging treatments for Alzheimer’s disease
Corbett, A., Smith, J. S., & Ballard, C. G. (2012) · Expert Review of Neurotherapeutics · doi:10.1586/ern.12.43 · Cited by 58
Dementia Pugilistica Revisited
Castellani, R. J., & Perry, G. L. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170669 · Cited by 65
Vaccination against β-Amyloid as a Strategy for the Prevention of Alzheimer’s Disease
Mantile, F., & Prisco, A. (2020) · Biology · doi:10.3390/biology9120425 · Cited by 56
“In the immunized participants the mean Aβ load was lower than in unimmunized controls matched for age at death [54].”
BackgroundInfluentialHumanin and the Receptors for Humanin
Matsuoka, M., & Hashimoto, Y. (2009) · Molecular Neurobiology · doi:10.1007/s12035-009-8090-z · Cited by 56
“A long-term follow-up report of a phase II clinical study with active immunization with Aβ indicated that prominent Aβ antibody-mediated reduction of brain Aβ levels did not preclude the progression of neurodegeneration in advanced AD cases [ 36 ].”
BackgroundWill anti-amyloid therapies work for Alzheimer's disease?
St George-Hyslop, P. H., & Morris, J. C. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61047-8 · Cited by 69
Recent advancement in therapeutic strategies for Alzheimer’s disease: Insights from clinical trials
Khan, T., Waseem, R., Shahid, M., Ansari, J., Ahanger, I. A., Hassan, M. I., & Islam, A. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102113 · Cited by 60
Caspase‐6 as a novel early target in the treatment of Alzheimer's disease
LeBlanc, A. C. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12250 · Cited by 56
“This could explain the absence of beneficial effects of the amyloid vaccine (Holmes et al., 2008).”
BackgroundMaftei, M., Thurm, F., Schnack, C., Tumani, H., Otto, M., Elbert, T. R., Kolassa, I., Przybylski, M., Manea, M., & Arnim, C. A. F. V. (2013) · PLoS ONE · doi:10.1371/journal.pone.0068996 · Cited by 54
Amyloid-Beta Disrupts Calcium and Redox Homeostasis in Brain Endothelial Cells
Fonseca, A. C., Moreira, P., Oliveira, C., Cardoso, S., Pinton, P., & Pereira, C. (2014) · Molecular Neurobiology · doi:10.1007/s12035-014-8740-7 · Cited by 56
“ases such as neprilysin and insulin-degrading enzyme seem to play a major role and is supported by studies such as those by Iwatsubo and colleagues performed in AD patients and transgenic mice [7–10].”
ResultMurakami, K., Tokuda, M., Suzuki, T., Irie, Y., Hanaki, M., Izuo, N., Monobe, Y., Akagi, K., Ishii, R., Tatebe, H., et al. (2016) · Scientific Reports · doi:10.1038/srep29038 · Cited by 55
Abbott, A. (2008) · Nature · doi:10.1038/456161a · Cited by 54
Tau acts as a mediator forAlzheimer's disease‐related synaptic deficits
Liao, D., Miller, E. C., & Teravskis, P. J. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12504 · Cited by 53
“Ab removal, reduction of Ab production and active immunization with Ab have shown limited efficacy, and do not prevent tau pathology or neurodegeneration (Green et al., 2009; Holmes et al., 2008).”
BackgroundMurakami, K. (2014) · Bioscience Biotechnology and Biochemistry · doi:10.1080/09168451.2014.940275 · Cited by 53
Valproic acid enhances microglial phagocytosis of amyloid-β1–42
Smith, A. M., Gibbons, H. M., & Dragunow, M. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.04.041 · Cited by 54
Beta-amyloid auto-antibodies are reduced in Alzheimer's disease
Qu, B.-X., Gong, Y., Moore, C., Fu, M., German, D. C., Chang, L.-Y., Rosenberg, R., & Diaz-Arrastia, R. (2014) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2014.06.017 · Cited by 47
“Active immunization with Aβ peptide increased blood anti-Aβ antibodies and thus decreased brain Aβ plaque burden in AD mouse models (Schenk et al., 1999; Morgan et al., 2000) as well as in AD patients (Gilman et al., 2005; Holmes et al., 2008).”
BackgroundAlzheimer's disease: Only prevention makes sense
Viña, J., & Sanz‐Ros, J. (2018) · European Journal of Clinical Investigation · doi:10.1111/eci.13005 · Cited by 55
Royea, J., & Hamel, É. (2020) · GeroScience · doi:10.1007/s11357-020-00231-y · Cited by 54
Mathur, R., Ince, P. G., Minett, T., Garwood, C. J., Shaw, P. J., Matthews, F. E., Brayne, C., Simpson, J. E., Wharton, S. B., & on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group (2015) · PLOS ONE · doi:10.1371/journal.pone.0118463 · Cited by 52
“The amyloid cascade hypothesis is currently the major theory of AD pathogenesis [48], however therapies based on removal of A have, to date, been disappointing [49].”
BackgroundHsu, P. J., Shou, H., Benzinger, T. L. S., Marcus, D., Durbin, T. J., Morris, J. C., & Sheline, Y. I. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-141743 · Cited by 53
Wang, L., Kang, H., Li, Y., Shui, Y., Yamamoto, R., Sugai, T., & Kato, N. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.12.033 · Cited by 51
“A review of a clinical trial in retrospect failed to demonstrate a clear correlation between cognitive improvement and plaque clearance in recipients of anti-amyloid vaccination (Schenk et al., 1999; Holmes et al., 2008).”
Perspectives on molecular targeted therapies and clinical trials for neurodegenerative diseases
Katsuno, M., Tanaka, F., & Sobue, G. (2012) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2011-301307 · Cited by 52
“Intriguingly, AN1792 reduced the amyloid plaque burden in the brains of AD patients compared with those of unvaccinated cases, suggesting that the active immunisation ameliorates AD pathology in humans.(8) The effects of this therapy on cognitive function were, however, not clearly shown in the phase 2a trial or in a…”
ResultBuechler, J., & Salinas, P. C. (2018) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2018.00038 · Cited by 53
Caspase-6 activity in the CA1 region of the hippocampus induces age-dependent memory impairment
LeBlanc, A. C., Ramcharitar, J., Afonso, V. M., Hamel, É., Bennett, D. A., Pakavathkumar, P., & Albrecht, S. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2013.194 · Cited by 51
“This could explain why removal of Ab in individuals with mild AD did not delay progression of the disease.(41)”
BackgroundCunningham, C. M., & Skelly, D. (2011) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-011-9312-5 · Cited by 51
“In contrast, the recent amyloid immunization clinical trial demonstrates that even very successful removal of amyloid plaques offers no relief to AD patients: all patients followed-up after the AN1792 study died with terminal dementia and an MMSE of zero (Holmes et al. 2008).”
BackgroundMethodVaccination as a Therapeutic Approach to Alzheimer's Disease
Wısnıewskı, T., & Boutajangout, A. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20156 · Cited by 53
Sacuiu, S. F. (2016) · Handbook of clinical neurology · doi:10.1016/b978-0-12-802973-2.00008-2 · Cited by 57
Monoclonal Antibody Against the Turn of the 42-Residue Amyloid β-Protein at Positions 22 and 23
Murakami, K., Horikoshi‐Sakuraba, Y., Murata, N., Noda, Y., Masuda, Y., Kinoshita, N., Hatsuta, H., Murayama, S., Shirasawa, T., Shimizu, T., et al. (2010) · ACS Chemical Neuroscience · doi:10.1021/cn100072e · Cited by 50
“Recently, a follow-up study has shown that immunization against Aβ42 suppressedAβ depositions inADpatients but not the progressive cognitive impairment (13).”
BackgroundAntibody Therapeutics Targeting Aβ and TauPreprint
Gallardo, G., & Holtzman, D. M. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a024331 · Cited by 55
Towards universal therapeutics for memory disorders
Sun, M., Nelson, T. J., & Alkon, D. L. (2015) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2015.04.004 · Cited by 51
Immunotherapy against amyloid pathology in Alzheimer's disease
Galimberti, D., Ghezzi, L., & Scarpini, E. A. (2013) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2012.12.013 · Cited by 50
Metadata
- Authors
- Holmes, C., Boche, D., Wilkinson, D., Yadegarfar, G., Hopkins, V., Bayer, A., Jones, R. W., Bullock, R., Love, S., Neal, J. W., Zotova, E., & Nicoll, J. A.
- Affiliations
- Moorgreen Hospital (GB)
- University of Southampton (GB)
- Isfahan University of Medical Sciences (IR)
- Royal United Hospital (GB)
- University of Bristol (GB)
- University of Wales (GB)
- University Hospital Southampton NHS Foundation Trust (GB)
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 372
- Issue
- 9634
- Pages
- 216-223
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2152446053
- Semantic Scholar
- 08e069e9f584a9125571b66eb799997753fe6d98
- Cited by
- 1,416
- References
- 33
- Citations by year
- 2026: 18 · 2025: 26 · 2024: 30 · 2023: 34 · 2022: 46 · 2021: 52 · 2020: 58 · 2019: 61 · 2018: 58 · 2017: 73 · 2016: 71 · 2015: 82 · 2014: 113 · 2013: 115 · 2012: 120
- FWCI
- 102.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- University of Oxford
- Medical Research Council
- 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 plaques, dental plaque removal, amyloid load, long-term clinical outcomes, survival, dementia progression, postmortem neuropathology, immunotherapy safety and efficacy, autopsy
- MeSH terms
- Aged, Alzheimer Disease, Antibody Formation, Follow-Up Studies, Humans, Randomized Controlled Trials as Topic, Amyloid beta-Peptides, Clinical Trials, Phase I as Topic, Plaque, Amyloid
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