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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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“parenchyma of the treated AD cases studied postmortem, this treatment had failed to reduce the number of neurofibrillary tangles and significantly alter the cognitive decline [19].”
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ResultCurrent and Emerging Drug Treatment Options for Alzheimerʼs Disease
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“Despite these facts, long-term examination of AD patients could not demonstrate a beneficial outcome after vaccination despite production of Ab-specific antibodies in these patients (Holmes et al., 2008).”
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“Our hypothesis may also help explain why interventions that benefit APP transgenic mice have thus far not benefited sporadic AD patients (Swerdlow, 2007a; Holmes et al., 2008).”
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“Method 1 Amyloid-b-immunolabelled sections from all cerebral cortical regions sampled were assessed for the specific histological features we previously associated with immunization-mediated plaque removal in Alzheimer’s disease (Table 2) (Nicoll et al., 2006; Holmes et al., 2008).”
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“Vascular Health and Risk Management 2012:8 obvious therapeutic targets, but successful interventions to prevent or remove amyloid plaques have not had the anticipated commensurate impacts on dementia.(2,3) It has been suggested that chronic brain hypoperfusion and consequent hypoxia/ischemia play a direct role in the…”
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“Recent reports of patients followed for several years are conflicting as they describe either no change in disease progression (Holmes et al., 2008) or a reduction in functional decline (Vellas et al.”
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“Removal of parenchymal Aβ plaques has historically been considered to be advantageous through limiting microglial-mediated inflammation, however, whilst recent Aβ immunisation trials were effective in reducing plaque burden, they did not prevent progressive neurodegeneration [53].”
ResultCinnamon extract inhibits tau aggregation associated with Alzheimer’s disease in vitro
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Report of the task force on designing clinical trials in early (predementia) AD
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Clinical and multimodal biomarker correlates of ADNI neuropathological findings
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“and a [57-59] and an increase of amyloid deposition in”
BackgroundUpdate on the Pharmacological Treatment of Alzheimers Disease
Massoud, F., & Gauthier, S. G. (2010) · Current Neuropharmacology · doi:10.2174/157015910790909520 · Cited by 168
“However, there was no association between antibody response, amyloid deposition, and clinical findings [11, 65].”
BackgroundO'Brien, J. T., & Burns, A. S. (2010) · Journal of Psychopharmacology · doi:10.1177/0269881110387547 · Cited by 166
Tampellini, D., Capetillo‐Zarate, E., Dumont, M., Huang, Z., Yu, F., Lin, M. T. S., & Gouras, G. K. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.3383-10.2010 · Cited by 165
“Although mouse behavior may not necessarily reflect human cognition, the aborted active A 42 vaccine clinical trial suggested a similar dissociation between plaques and cognition, with plaque clearance despite continued cognitive decline (Holmes et al., 2008).”
BackgroundImpaired cerebral vasoreactivity to CO2 in Alzheimer's disease using BOLD fMRI
Cantin, S., Villien, M., Moreaud, O., Troprés, I., Keignart, S., Chipon, E., Bas, J. F. L., Warnking, J. M., & Krainik, A. (2011) · NeuroImage · doi:10.1016/j.neuroimage.2011.06.070 · Cited by 168
“Recent failure in AD immunotherapy (Holmes et al., 2008) has reinforced the hypothesis of the harmful structural role of the amyloid protein.”
BackgroundSerrano-Pozo, A., William, C. M., Ferrer, I., Uro-Coste, E., Delisle, M.-B., Maurage, C.-A., Hock, C., Nitsch, R. M., Masliah, E., Growdon, J. H., et al. (2010) · Brain · doi:10.1093/brain/awq056 · Cited by 159
“…have yielded conflicting results, with no difference in the rates of survival to death and progression to severe dementia in subjects from an earlier phase 1 trial (Holmes et al., 2008) and a reduced rate of functional decline in a subset of subjects from the phase 2a trial (Vellas et al., 2009).”
BackgroundResultInfluentialRitchie, C. W., Smailagic, N., Noel-Storr, A. H., Takwoingi, Y., Flicker, L. A., Mason, S., & McShane, R. H. (2014) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd008782.pub4 · Cited by 167
Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases
Lleó, A., Cavedo, E., Parnetti, L., Vanderstichele, H., Herukka, S., Andreasen, N., Ghidoni, R., Lewczuk, P., Jeromin, A., Winblad, B. G., et al. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.232 · Cited by 162
The Vascular Hypothesis of Alzheimer’s Disease: Bench to Bedside and Beyond
de la Torre, J. C. (2010) · Neurodegenerative Diseases · doi:10.1159/000285520 · Cited by 164
Lord, A., Gumucio, A., Englund, H., Sehlin, D., Sundquist, V. S., Söderberg, L., Möller, C., Gellerfors, P., Lannfelt, L., Pettersson, F. E., et al. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.08.007 · Cited by 158
“However, in more recent studies on the longterm effects of the AN1792 vaccine, there was no evidence of delayed disease progression despite amyloid plaque clearance and high antiAβ antibody titres (Holmes et al., 2008).”
BackgroundA canine model of human aging and Alzheimer's disease
Head, E. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.03.016 · Cited by 177
Apomorphine treatment in Alzheimer mice promoting amyloid‐β degradation
Himeno, E., Ohyagi, Y., Ma, L., Nakamura, N., Miyoshi, K., Sakae, N., Motomura, K., Soejima, N., Yamasaki, R., Hashimoto, T., et al. (2010) · Annals of Neurology · doi:10.1002/ana.22319 · Cited by 155
“Also, long-term clinical efficacy of Ab immunization has not been observed despite certain improvements in pathology.(4) Many of these therapies target extracellular Ab fibrils, and new therapeutic strategies for AD are still under development.”
BackgroundAnthony, I. C., Norrby, K. E., Dingwall, T., Carnie, F. W., Millar, T., Arango, J. C., Robertson, R., & Bell, J. E. (2010) · Brain · doi:10.1093/brain/awq263 · Cited by 156
Amyloid-β immunisation for Alzheimer's disease
Wisniewski, T., & Konietzko, U. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70170-4 · Cited by 155
Alzheimer’s disease, cerebrovascular disease, and the β-amyloid cascade
Honjo, K., Black, S. E., & Verhoeff, N. P. L. G. (2012) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100015547 · Cited by 152
Neurobiological pathways to Alzheimer's disease: Amyloid-beta, TAU protein or both?
de Paula, V. D. J. R., Guimarães, F. M., Diniz, B. S., & Forlenza, O. V. (2009) · Dementia & Neuropsychologia · doi:10.1590/s1980-57642009dn30300003 · Cited by 162
“Since late-onset AD (LOAD) represents the vast majority of cases, and considering that amyloidogenesis in these patients occurs to a lesser extent compared to the early AD, questions have been raised concerning the appropriateness of EOAD models to aid understanding of LOAD.42”
Libri, V., Yandım, C., Athanasopoulos, S., Loyse, N., Natisvili, T., Law, P. P., Chan, P. K., Mohammad, T., Mauri, M., Tam, K. T., et al. (2014) · The Lancet · doi:10.1016/s0140-6736(14)60382-2 · Cited by 156
Biological Marker Candidates of Alzheimer's Disease in Blood, Plasma, and Serum
Schneider, P., Hampel, H. J., & Büerger, K. (2009) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2009.00104.x · Cited by 154
“In another randomized placebo-controlled trial investigating active immunization with AN1792 in AD patients [37], mean anti-Aβ antibody titers were also raised in the treatment versus the placebo group (P = 0.”
BackgroundTakeuchi, H., Mizoguchi, H., Doi, Y., Jin, S., Noda, M., Liang, J., Li, H., Zhou, Y., Mori, R., Yasuoka, S., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021108 · Cited by 149
Amyloid β oligomers (AβOs) in Alzheimer’s disease
Mroczko, B., Groblewska, M., Litman‐Zawadzka, A., Kornhuber, J., & Lewczuk, P. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1820-x · Cited by 150
Drug development for Alzheimer's disease: where are we now and where are we headed?
Sabbagh, M. N. (2009) · The American journal of geriatric pharmacotherapy · doi:10.1016/j.amjopharm.2009.06.003 · Cited by 147
de la Torre, J. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-180004 · Cited by 161
Desensitization of nicotinic acetylcholine receptors as a strategy for drug development
Buccafusco, J. J., Beach, J. W., & Terry, A. V. (2009) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.108.145292 · Cited by 144
“With the amyloid hypothesis in doubt (Holmes et al., 2008), the search for compounds that can both improve cognition and produce neuroprotection, possibly slowing the disease process, becomes paramount.”
BackgroundWhy Pleiotropic Interventions are Needed for Alzheimer's Disease
Frautschy, S. A., & Cole, G. M. (2010) · Molecular Neurobiology · doi:10.1007/s12035-010-8137-1 · Cited by 152
Biomarkers in Alzheimer's disease drug development
Blennow, K. (2010) · Nature Medicine · doi:10.1038/nm.2221 · Cited by 145
Copper Toxicity Links to Pathogenesis of Alzheimer’s Disease and Therapeutics Approaches
Ijaz, H. W., Wang, W., & Lang, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207660 · Cited by 146
Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease
Wang, M., Zhang, H., Liang, J., Huang, J., & Chen, N. (2023) · Journal of Neuroinflammation · doi:10.1186/s12974-023-02753-6 · Cited by 154
“Many developed drugs have not shown the positive therapeutic effects on AD patients and even can cause severe adverse reactions, such as meningitis [31] and cognitive impairment [32].”
BackgroundCerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease
Weller, R. O., Preston, S., Subash, M., & Carare, R. O. (2009) · Alzheimer s Research & Therapy · doi:10.1186/alzrt6 · Cited by 148
“However, despite the removal of Aβ plaques from the brain, there is little evidence that this benefits cognitive function [69].”
BackgroundVlassenko, A. G., Mintun, M. A., Xiong, C., Sheline, Y. I., Goate, A., Benzinger, T. L. S., & Morris, J. C. (2011) · Annals of Neurology · doi:10.1002/ana.22608 · Cited by 148
“However, candidate disease-modifying drugs that target Ab have yet to demonstrate efficacy in persons with symptomatic AD, even when it appears that the treatment may succeed in reducing cerebral Ab burden.(2) It is possible that the failure to date of anti-Ab therapies to benefit individuals with clinically diagnosed…”
BackgroundLong-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease
Farlow, M. R., Andreasen, N., Riviere, M., Voštiar, I., Vitaliti, A., Sóvágó, J., Caputo, A., Winblad, B. G., & Graf, A. (2015) · Alzheimer s Research & Therapy · doi:10.1186/s13195-015-0108-3 · Cited by 149
“Continuous exposure to antibody titers through regular injections, along with targeting earlier disease stages, might increase the likelihood of positive effects on clinical outcomes [17,29].”
BackgroundDá Mesquita, S., Ferreira, A. C., Sousa, J. C., Correia-Neves, M., Sousa, N., & Marques, F. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.014 · Cited by 166
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
Amyloid β-42 induces neuronal apoptosis by targeting mitochondria
Han, X., Hu, Y., Yang, Z., Jiang, L., Shi, S.-L., Li, Y.-R., Guo, M., Wu, H., & Wan, Y. (2017) · Molecular Medicine Reports · doi:10.3892/mmr.2017.7203 · Cited by 146
“Of these, A β -42 and A β -43 are considered neurotoxic (9,10).”
Mielke, M. M., & Lyketsos, C. G. (2010) · NeuroMolecular Medicine · doi:10.1007/s12017-010-8121-y · Cited by 143
“…showing that despite a greatly reduced amyloid-beta plaque load in actively immunized AD patients treated with AN1792 (Elan Pharmaceuticals), there was no evidence of improved survival or of an improvement in the time to severe dementia in the treated versus the placebo group (Holmes et al. 2008).”
BackgroundAbnormal Cognition, Sleep, EEG and Brain Metabolism in a Novel Knock-In Alzheimer Mouse, PLB1
Platt, B., Drever, B. D., Koss, D. J., Stoppelkamp, S., Jyoti, A., Plano, A., Utan, A., Merrick, G., Ryan, D., Melis, V., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027068 · Cited by 147
“). Consistently, clearance of plaques (e.g. by immunisation or secretase inhibition) did not benefit cognition”
Background
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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