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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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“…loss, caspas secretase inhibitors, may ultimately be successful, in clinical trials thus far these approaches have often been shown to have substantial side effects and toxicities, and have not ameliorated disease symptoms (Holmes et al., 2008; Orgogozo et al., 2003; Serrano-Pozo et al., 2010).”
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“Taken together, AN-1792 follow-up studies of immunized patients have suggested that even extensive senile plaque disruption might yield at best only modest and temporary clinically quantifiable cognitive improvement [30,43,44].”
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“post-mortem results from patients enrolled in an early amyloid antibody study demonstrate that substantial reduction in amyloid load did not result in improvement in cognitive status nor apparent delays in disease progression (Holmes et al. 2008).”
BackgroundPrevention approaches in a preclinical canine model of Alzheimer’s disease: benefits and challenges
Davis, P. R., & Head, E. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00047 · Cited by 43
“The most recent autopsy study of eight patients that were in the AN1792 study further confirm reduced Aβ pathology in response to treatment, 5 years after the last injection (Holmes et al., 2008).”
ResultQu, A., Huang, F., Li, A., Yang, H., Zhou, H., Long, J., & Shi, L. (2016) · Chemical Communications · doi:10.1039/c6cc07803f · Cited by 42
Amyloid-β and α-Synuclein Immunotherapy: From Experimental Studies to Clinical Trials
Nimmo, J., Kelly, L., Verma, A. K., Carare, R. O., Nicoll, J. A. R., & Dodart, J. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.733857 · Cited by 40
“An extension study in 62% patients used a modified formulation of AN1792 by replacing QS-21 with polysorbate80, which increased the antibody titre response to 59% (Bayer et al., 2005; Holmes et al., 2008).”
BackgroundMethodSelf-citationBasi, G. S., Feinberg, H., Oshidari, F., Anderson, J., Barbour, R., Baker, J., Comery, T. A., Diep, L., Gill, D. S., Johnson‐Wood, K., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.045187 · Cited by 45
Brain targeting based nanocarriers loaded with resveratrol in Alzheimer's disease: A review
Jalili, C., Kiani, A., Gholami, M., Bahrehmand, F., Fakhri, S., Kakehbaraei, S., & Kakebaraei, S. (2023) · IET Nanobiotechnology · doi:10.1049/nbt2.12127 · Cited by 43
“Moreover, an imbalance between Aβ production and its removal plays a fundamental role in the progression of AD [11].”
BackgroundAlzheimer’s Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?
Høilund‐Carlsen, P. F., Alavi, A. A., Castellani, R. J., Neve, R. L., Perry, G. L., Revheim, M.-E. R., & Barrio, J. R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25073892 · Cited by 44
Biomarkers and evolution in Alzheimer disease
Rapoport, S. I., & Nelson, P. T. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.07.006 · Cited by 40
“Frustration based on these limitations is palpable in this volume, especially in view of early expectations of effective therapy based on the amyloid hypothesis, which have not been born out (Fleisher et al., 2008; Holmes et al., 2008).”
Backgroundβ‐amyloid cortical deposits are accompanied by the loss of serotonergic neurons in the dog
Bernedo, V., Insua, D., Suarez, M. L., Santamarina, G., Sarasa, M., & Pesini, P. (2009) · The Journal of Comparative Neurology · doi:10.1002/cne.21985 · Cited by 40
“Therefore, although ascending projections from the DRN and MRN overlap extensively, differences in their relative contributions to particular regions have been reported (Bobillier et al., 1976; Waterhouse et al., 1986; Kosofsky and Molliver, 1987; Wilson and Molliver, 1991; Hornung, 2003).”
BackgroundConsidering a new paradigm for Alzheimer's disease research
Langley, G. R. (2014) · Drug Discovery Today · doi:10.1016/j.drudis.2014.03.013 · Cited by 42
“Nature 400, 173–177 79 Holmes, C. et al. (2008) Long-term effects of Abeta42 immunisation in Alzheimer’s”
Boche, D., & Nicoll, J. A. R. (2020) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12642 · Cited by 41
Self-citationTakata, K., Ginhoux, F., & Shimohama, S. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114754 · Cited by 40
Kojro, E., & Postina, R. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0998 · Cited by 40
Xu, J., Sato, S., Okuyama, S., Swan, R. J., Jacobsen, M. T., Strunk, E., & Ikezu, T. (2010) · The FASEB Journal · doi:10.1096/fj.09-150144 · Cited by 43
“However, the possibility of using it as a therapeutic target has grown more important after recent unsuccessful reports on the phase II trial of A vaccination in AD patients, which show successful A removal from brain but a lack of beneficial effects on disease progression (33).”
BackgroundGouras, G. K., Willén, K., & Tampellini, D. (2012) · Life Sciences · doi:10.1016/j.lfs.2012.06.004 · Cited by 39
Cairns, N. J., Taylor‐Reinwald, L., Morris, J. C., & Initiative, A. D. N. (2010) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.03.012 · Cited by 39
Immunotherapies in Alzheimer’s disease: Too much, too little, too late or off-target?
St‐Amour, I., Cicchetti, F., & Calon, F. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1518-9 · Cited by 40
“Despite a significant reduction of the amyloid burden identified by postmortem histological analyses, the assessment of the cognitive performance of remaining participants to the AN1792 study failed to highlight an impact on disease progression [56, 104].”
BackgroundWang, Y.-J., Gao, C.-Y., Yang, M., Liu, X.-H., Sun, Y., Pollard, A., Dong, X.-Y., Wu, X.-B., Zhong, J.-H., Zhou, H.-D., et al. (2010) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2010.05.010 · Cited by 41
“Recently, a 6-year prospective follow-up study of the first phase 1 clinical trial of active Ab immunization reported that the generation of anti-Ab antibodies was elicited and cortical Ab plaques were subsequently removed in an antibody-titer-dependent manner after immunization with Ab (Holmes et al., 2008).”
BackgroundVaccination against Alzheimer disease
Fettelschoss‐Gabriel, A., Zabel, F., & Bachmann, M. F. (2014) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.28183 · Cited by 39
“Hence, as in the transgenic mice, specific IgG was able to remove plaques consisting of Aβ 1-42 from the brain.(23) This was an important finding as many researchers doubted the ability of serum IgG antibodies to interfere with plaque burden in a secluded place such as the brain.”
BackgroundPanza, F., Frisardi, V., Imbimbo, B. P., Seripa, D., Solfrizzi, V., & Pilotto, A. (2011) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2011.579099 · Cited by 38
“However, the hypothesis that Ab is the key pathologic factor affecting the disease process is strongly questioned by the finding that immunization with pre-aggregated Ab1--42 (AN1792) resulted in almost complete removal of the Ab plaques from the brain of the patients but did not prevent progressive cognitive and clin…”
BackgroundAnti-tau oligomers passive vaccination for the treatment of Alzheimer disease
Kayed, R. (2010) · Human Vaccines · doi:10.4161/hv.6.11.12689 · Cited by 38
Dissecting Molecular Mechanisms in the Living Brain of Dementia Patients
Barrio, J. R., Satyamurthy, N., Huang, S., Petrič, A., Small, G. W., & Kepe, V. (2009) · Accounts of Chemical Research · doi:10.1021/ar800189x · Cited by 38
Goldman, J. G., Aggarwal, N. T., & Schroeder, C. (2015) · Neurodegenerative Disease Management · doi:10.2217/nmt.15.34 · Cited by 40
Chua, S. W., Cornejo, A., van Eersel, J., Stevens, C. H., Vaca, I., Cueto, M., Kassiou, M., Gladbach, A., Macmillan, A., Lewis, L., et al. (2017) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.6b00433 · Cited by 38
Downregulated apoptosis and autophagy after anti‐Aβ immunotherapy in Alzheimer's disease
Paquet, C., Nicoll, J. A. R., Love, S., Mouton‐Liger, F., Holmes, C., Hugon, J., & Boche, D. (2017) · Brain Pathology · doi:10.1111/bpa.12567 · Cited by 40
“This may explain the absence of clinical amelioration in these patients (19).”
BackgroundMethodResultInfluentialSelf-citationPrasanth, M. I., Malar, D. S., Tencomnao, T., & Brimson, J. M. (2021) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2021.1939681 · Cited by 40
“brain but did not slow dementia progression [124].”
BackgroundImmunotherapeutic approaches for Alzheimer’s disease in transgenic mouse models
Wısnıewskı, T., & Boutajangout, A. (2009) · Brain Structure and Function · doi:10.1007/s00429-009-0236-2 · Cited by 39
“…404 Subcutaneously with alum adjuvant Asuni et al. (2007) Human tau PS1 Tau peptide 379–408, phosphorylated at Ser 396, Ser 404 Subcutaneously with alum adjuvant Boutajangout et al. (2008) was no evidence of improved survival or an improvement in the time to severe dementia (Holmes et al. 2008).”
BackgroundMethodTakashima, A. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2012.00047 · Cited by 39
“However, contrary to these results, recent clinical trials show that reducing Aβ generation, or removing Aβ deposits fail to halt the progression of dementia (Holmes et al., 2008).”
Voluntary exercise counteracts Aβ25-35-induced memory impairment in mice
Wang, Q. L., Xu, Z., Tang, J., Sun, J., Gao, J., Wu, T., & Xiao, M. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.09.024 · Cited by 39
Anti-amyloid-beta to tau-based immunization: developments in immunotherapy for Alzheimer's disease
Lambracht‐Washington, D., & Rosenberg, R. N. (2013) · ImmunoTargets and Therapy · doi:10.2147/itt.s31428 · Cited by 39
Pharmacokinetics and Pharmacodynamics of CHF5074 After Short-term Administration in Healthy Subjects
Imbimbo, B. P., Frigerio, E., Breda, M., Fiorentini, F., Fernández, M., Sivilia, S., Giardino, L., Calzà, L., Norris, D., Casula, D., et al. (2012) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e3182622ace · Cited by 37
Varamini, B., Sikalidis, A. K., & Bradford, K. L. (2013) · International Journal of Food Sciences and Nutrition · doi:10.3109/09637486.2013.832171 · Cited by 38
“In humans, a number of studies show that progressive neurodegeneration may occur in AD patients despite removal of plaques, and many cognitively normal humans display Ab plaques in equivalent densities as Alzheimer’s diseased individuals (Davis et al., 1999; Holmes et al., 2008).”
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
Self-citationAmyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds
Joseph‐Mathurin, N., Dorieux, O., Trouche, S. G., Boutajangout, A., Kraska, A., Fontès, P., Verdier, J., Sigurdsson, E. M., Mestre‐Francés, N., & Dhénain, M. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.05.013 · Cited by 38
Scheffler, K., Stenzel, J., Krohn, M., Lange, C., Hofrichter, J., Schumacher, T., Brüning, T., Plath, A.-S., Walker, L. C., & Pahnke, J. (2011) · Current Alzheimer Research · doi:10.2174/156720511797633179 · Cited by 37
“Indeed, recent analyses suggest that CAA, which increases in the early stages of plaque removal, also may be eliminated by immunotherapy after an extended period of time [24].”
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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