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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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Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer's Disease
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“Although immunisation with Ab42 resulted in clearance of amyloid plaques in patients with AD, this clearance did not prevent progressive neurodegeneration (Holmes et al. 2008).”
BackgroundRetractedDEFINING DISEASE MODIFYING THERAPY FOR ALZHEIMER’S DISEASE
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript status were generally lacking (Holmes et al. 2008), and an early trial, AN1792, was halted due to a serious adverse event of meningoencephalitis in multiple participants (Senior 2002).”
BackgroundBiomarkers for Alzheimer's disease therapeutic trials
Hampel, H. J., Wilcock, G. K., Andrieu, S., Aisen, P. S. S., Blennow, K., Broich, K., Carrillo, M. C., Fox, N. C., Frisoni, G. B., Isaac, M., et al. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.11.005 · Cited by 140
“The relationship of plaque load to clinical efficacy has been questioned by the phase I AN1792 immunotherapy trial follow-up report in which a small number of participants who died several years after the trial was completed showed apparent reduction in amyloid load despite progression of their dementia at autopsy (Ho…”
Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease
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“Much has been made of the fact that the first immunisation trials were successful in clearing the Ab from the brain in humans, as they had done in mice, but had no large effect on the clinical symptoms suggesting that Ab clearance in late stage disease is not a miraculous cure (Schenk et al. 1999; Holmes et al. 2008).”
BackgroundCortical hypermetabolism in MCI subjects: a compensatory mechanism?
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“Further, data from recent human studies have shown that in a small subset of AD subjects, the removal of plaques by vaccination does not ameliorate memory function [16].”
ResultStrategies for the Inhibition of Protein Aggregation in Human Diseases
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“We previously demonstrated Aβ clearance in a subset of AN1792 patients 3–5 , 16 .”
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“A follow-up study of the long term effect of this drug in AD revealed a significantly lower Aβ volume in the brain of AD patients, however no significant improvement in the symptoms of dementia [163].”
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Clayton, K. A., Enoo, A. A. V., & Ikezu, T. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00680 · Cited by 137
“However, considerable evidence has suggested this pursuit may be clinically ineffective—decreasing amyloid burden in patients with an already significant degree of cognitive deficits, and hence neurodegeneration, does not appear to dampen the rate of decline (Holmes et al., 2008).”
BackgroundNew Insights Into Drug Discovery Targeting Tau Protein
Soeda, Y., & Takashima, A. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.590896 · Cited by 136
“These have been driven by the fact that phase 3 clinical trials for AD using Aβ-targeted drugs failed to reach their primary predicted outcome (Holmes et al., 2008; Rosenblum, 2014).”
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“3 However, amyloid plaques correlate poorly with memory decline 4 and immunotherapy-induced plaque removal may not prevent progressive neurodegeneration 5 suggesting that other entities may be required for AD-related degeneration.”
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“Although Aβ immunotherapy has resulted in the clearance of amyloid plaques in ADpatients, this clearance has not always resulted in significant reduction of progressive neurodegeneration (Holmes et al., 2008).”
BackgroundDevelopment of AFFITOPE vaccines for Alzheimer's disease (AD) — From concept to clinical testing
Schneeberger, A., Mandler, M., Otava, O., Zauner, W., Mattner, F., & Schmidt, W. (2009) · The journal of nutrition health & aging · doi:10.1007/s12603-009-0070-5 · Cited by 130
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“In 2008, a paper was published describing the relationship between Ab42 immune response, degree of plaque removal and long-term clinical outcomes [Holmes et al. 2008].”
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“…post-mortem neuropathological examination of Ab1-42 immunization in AD patients showed that although immunization with Ab1-42 resulted in reduction of amyloid plaques in patients with AD, this reduction did not prevent progressive neurodegeneration and cognitive decline (Holmes et al., 2008).”
Tau‐targeted treatment strategies in Alzheimer's disease
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“Whether these approaches will lead to the anticipated outcome remains to be seen as for those human cases from the first trial that were followed up no cognitive benefits of the amyloid clearance could be detected (Holmes et al., 2008).”
BackgroundFournier, A. E., Oprisiu, R., Sérot, J., Godefroy, O., Achard, J., Faure, S., Mazouz, H., Temmar, M., Albu, A., Bordet, R., et al. (2009) · Expert Review of Neurotherapeutics · doi:10.1586/ern.09.89 · Cited by 131
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“Much interest has been shown in Aβ and its removal from the brain via natural methods or vaccination [58]; CD163 immunoreactive microglia clusters around Aβ plaques support the idea that they might serve a similar purpose.”
BackgroundNeuronal death in Alzheimer’s disease and therapeutic opportunities
Donev, R., Kolev, M. V., Millet, B., & Thome, J. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00889.x · Cited by 126
“Furthermore, despite the apparent success in amyloid clearance, the clinical cognitive benefits from the vaccination were very modest compared to the placebo group [244, 245].”
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Treatment Strategies Targeting Amyloid -ProteinPreprint
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“In eight of these progressing subjects who were autopsied, two showed no apparent decrease in plaque burden, four had intermediate decreases, and two had marked decreases (Holmes et al. 2008).”
BackgroundImmunotherapy for Alzheimer‘s Disease: From Anti-β-Amyloid to Tau-Based Immunization Strategies
Panza, F., Frisardi, V., Solfrizzi, V., Imbimbo, B. P., Logroscino, G., Santamato, A., Greco, A., Seripa, D., & Pilotto, A. (2012) · Immunotherapy · doi:10.2217/imt.11.170 · Cited by 130
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“Since Ab and s targeting treatment strategies against AD have been unsuccessful to date [22, 32, 48] GVD presumably will be important for the understanding of ADrelated pathomechanisms as well as for the identification of alternative therapeutic targets.”
BackgroundAlzheimer's Disease is Incurable but Preventable
de la Torre, J. C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-091579 · Cited by 131
The Role of PICALM in Alzheimer’s Disease
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Dodel, R. C., Balakrishnan, K., Keyvani, K., Deuster, O., Neff, F., Andrei‐Selmer, L., Röskam, S., Stüer, C., Al‐Abed, Y., Noelker, C., et al. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.4401-10.2011 · Cited by 129
“In patients treated with antibodies directed against the N terminus of A , a considerable decrease in plaque load has been reported, but clearance of already formed plaques might not be sufficient to improve cognitive function in AD patients (Holmes et al., 2008).”
BackgroundThe amyloid cascade and Alzheimer's disease therapeutics: theory versus observation
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“Eliminating amyloid deposits via Ab immunization may represent a cure in Tg mice, but regardless of the apparent total disruption of senile plaques in immunized patients with SAD, the successful clearance of these structures could neither reverse nor halt the progression of dementia [1].”
InfluentialDisease-Modifying Therapies for Alzheimer’s Disease: More Questions than Answers
Golde, T. E. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01201-2 · Cited by 119
“Additional studies on larger cohorts of AN-1792 vaccinated individuals also claim reductions in amount of amyloid deposited in some areas of the brain, relative to what might be expected [23, 25]; however, this data is again circumstantial.”
BackgroundResultAmyloid-β Peptide: Dr. Jekyll or Mr. Hyde?
Puzzo, D., & Arancio, O. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129033 · Cited by 134
Pharmacological Treatment of Alzheimer Disease
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Neuroinflammation in Alzheimer’s disease: insights from peripheral immune cells
Zhang, Q., Yang, G., Luo, Y., Jiang, L., Chi, H., & Tian, G. (2024) · Immunity & Ageing · doi:10.1186/s12979-024-00445-0 · Cited by 138
“Although these antibodies can reduce amyloid plaques, they have not significantly reversed cognitive impairments [219].”
BackgroundCurrent therapeutic targets for the treatment of Alzheimer’s disease
Grill, J. D., & Cummings, J. L. (2010) · Expert Review of Neurotherapeutics · doi:10.1586/ern.10.29 · Cited by 123
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APP/Aβ structural diversity and Alzheimer's disease pathogenesis
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“Interestingly, Holmes et al. (2008). reported that some cases exhibited an almost complete absence of histologically visible amyloid deposits.”
Influential(2012) · doi:10.1038/nrneurol.2012.118 · Cited by 122
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
“This interpretation might also be applied to the results of the AN-1792 clinical trials, in which low levels of amyloid in several treated patients were taken to suggest evidence for plaque clearance (Nicoll et al., 2003, 2006; Holmes et al., 2008).”
ResultShinohara, M., Sato, N., Kurinami, H., Takeuchi, D., Takeda, S., Shimamura, M., Yamashita, T., Uchiyama, Y., Rakugi, H., & Morishita, R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.102277 · Cited by 122
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“These observations bolstered the clinical development of A immunotherapy for treatment of AD, although a long-term follow-up study of A immunization in patients with AD showed that clearance of A deposits did not necessarily prevent progressive neurodegeneration (Holmes et al., 2008).”
BackgroundInsulin Signaling Impairment in the Brain as a Risk Factor in Alzheimer’s Disease
Hölscher, C. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00088 · Cited by 122
“This could explain why the removal of amyloid plaques from the brains of AD patients did not stop disease progression (Holmes et al., 2008).”
BackgroundAmyloid‐β associated volume loss occurs only in the presence of phospho‐tau
Desikan, R. S., McEvoy, L. K., Thompson, W. K., Holland, D., Roddey, J. C., Blennow, K., Aisen, P. S. S., Brewer, J. B., Hyman, B. T., & Dale, A. M. (2011) · Annals of Neurology · doi:10.1002/ana.22509 · Cited by 118
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Progress and Developments in Tau Aggregation Inhibitors for Alzheimer Disease
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Nelson, P. T., Abner, E. L., Schmitt, F. A., Kryscio, R. J., Jicha, G. A., Santacruz, K., Smith, C. D., Patel, E., & Markesbery, W. R. (2009) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181aacbe9 · Cited by 115
“Furthermore, there is suggestion from human A-beta vaccination studies that amyloid-negative NFT-positive cases can progress to end-stage AD (67).”
Tau as a therapeutic target in neurodegenerative disease
Himmelstein, D. S., Ward, S., Lancia, J. K., Patterson, K. R., & Binder, L. I. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.07.001 · Cited by 122
“However, the clearance of Aβ plaques has been shown to have limited effect attenuating cognitive decline once Alzheimer symptoms are already underway (Holmes et al., 2008).”
Assessing the contribution of inflammation in models of Alzheimer's disease
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BackgroundGeneration and Therapeutic Efficacy of Highly Oligomer-Specific β-Amyloid Antibodies
Hillen, H., Barghorn, S., Striebinger, A., Labkovsky, B., Müller, R., Nimmrich, V., Nolte, M. W., Perez-Cruz, C., van der Auwera, I., van Leuven, F., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5721-09.2010 · Cited by 113
“Amyloid plaque removal seems unable to stop ongoing dementia in AD patients (Holmes et al., 2008).”
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“With multiple failed clinical trials targeted at removing amyloid-β from the brain, researchers have turned to other possible hypotheses to explain the cause of Alzheimer’s disease (Holmes et al., 2008; Karran et al., 2011).”
BackgroundDavtyan, H., Ghochikyan, A., Petrushina, I., Hovakimyan, A., Davtyan, A., Poghosyan, A., Marleau, A. M., Movsesyan, N., Kiyatkin, A., Rasool, S., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4672-12.2013 · Cited by 112
“DOI:10.1523/JNEUROSCI.4672-12.2013 Copyright © 2013 the authors 0270-6474/13/334923-12$15.00/0 accounted for the low antibody titers in many patients in the AN1792 trial (Nicoll et al., 2003; Ferrer et al., 2004; Gilman et al., 2005; Boche et al., 2008; Holmes et al., 2008).”
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“Postmortem examination revealed T cells primarily in meningeal areas in which Ab had accumulated (Nicoll et al., 2003), as well as drainage of Ab to the vasculature (Boche et al., 2008; Holmes et al., 2008).”
BackgroundNovel insights for the treatment of Alzheimer's disease
Kurz, A., & Perneczky, R. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.07.018 · Cited by 115
“, 2003) without achieving an impact on the clinical course (Holmes et al., 2008).”
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“Unfortunately, however, in humans clearance of amyloid plaques in AD patients had no influence on the progression of dementia and did not affect tau-pathology within the lesions (Holmes et al. 2008).”
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“Although the AN1792 clinical trial failed, long-term follow-up of responder patients showed a reduction in brain amyloid burden [27, 28] and attenuated functional decline [29–31], which supports the potential benefits of Aβ immunotherapy, provided that an Aβ-specific T-cell response can be avoided.”
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“There remains no established way of slowing the disease, and based on preliminary findings [9], many have expressed the concern that existing anti-amyloid approaches in patients with frank dementia have been “too little too late” to maximize their potential beneficial effects.”
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Dodel, R. C., Neff, F., Noelker, C., Pul, R., Du, Y., Bacher, M., & Oertel, W. H. (2010) · Drugs · doi:10.2165/11533070-000000000-00000 · Cited by 113
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“The A𝛽 can also act as an antigen activating adaptive responses, because mounting reports described A𝛽reactive circulating B cells in patients with AD [175].”
BackgroundDisease modification and Neuroprotection in neurodegenerative disorders
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“In AD, removal of plaque amyloid has been demonstrated with several immunotherapies with no corresponding clinical benefit and reducing fibrillar amyloid demonstrated with amyloid imaging is not by itself support of DM [31, 32].”
BackgroundThe Role of Mitochondrial Calcium Homeostasis in Alzheimer’s and Related Diseases
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“Importantly, CAA severity correlates with degree of dementia in humans (Attems et al. 2005), although there has been much debate about whether CAA is a driving force in the pathobiology of AD. Yet, CAA may represent an important therapeutic target in AD. Recently, Hawkes and McLaurin showed that a perivascular subset…”
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“Disappointingly, however, the patients failed to show a long term cognitive benefit of the vaccination [34].”
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“Results of another 6-year followup study on AN1972 showed that progression to severe AD stages was not prevented in immunised patients, and there was no evidence of improved survival despite a reduction of the Aβ load [44].”
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“This was indicated in one study by the fact that Aβ vaccination almost entirely cleared Aβ, whilst the severe and progressive tangle pathology remained and clinical improvement was not achieved [81].”
The Ontario Neurodegenerative Disease Research Initiative (ONDRI)
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“Such confirmation has not yet been replaced by other diagnostic approaches because recent data indicate that more than 10% of patients entering clinical trials for treatment of AD suffer from other conditions.(32) Beyond the categorical diagnosis, the neuropathological assessment will also document the extent to which…”
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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