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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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BackgroundA critical overview of therapeutic strategy and advancement for Alzheimer's disease treatment
Kuo, Y., & Rajesh, R. (2017) · Journal of the Taiwan Institute of Chemical Engineers · doi:10.1016/j.jtice.2017.05.011 · Cited by 15
Humanin Signal for Alzheimer's Disease
Matsuoka, M. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-102076 · Cited by 16
Delatour, B., Epelbaum, S., Petiet, A., & Dhénain, M. (2010) · International Journal of Alzheimer s Disease · doi:10.4061/2010/604853 · Cited by 18
“In addition there is, today, no conclusive evidence to support the hypothesis that reducing amyloid load by stimulating plaque clearance has any clinical effects in AD patients [91].”
BackgroundAD Vaccines: Conclusions and Future Directions
Wisniewski, T. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787847289 · Cited by 14
Emerging Roles of T Helper Cells in Non-Infectious Neuroinflammation: Savior or Sinner
Liu, W., Fan, M., Lu, W., Zhu, W., Meng, L., & Lu, S. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.872167 · Cited by 16
Advances of therapy for Alzheimer's disease: An updated review
Mei, C., Zhan, J., Zhu, S., Zhang, Y., Xiong, C., Wang, J., Xu, Y. J., Zhong, H., & Cheng, J. (2024) · Brain‐X · doi:10.1002/brx2.68 · Cited by 15
Knezović, A., & Šalković‐Petrišić, M. (2025) · Journal of Neural Transmission · doi:10.1007/s00702-025-02887-2 · Cited by 15
“…the exact cause of sAD is yet unknown, literature data indicate that the amyloid hypothesis might not apply to sAD ethiopathogen - esis and that Aβ overproduction and alterations of respec - tive genes seem not to be the primary pathophysiological event in sAD (Holmes et al. 2008; Hardy 2009).”
Lambracht‐Washington, D., & Rosenberg, R. N. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.12.011 · Cited by 14
Xiong, C., van Belle, G., Chen, K., Tian, L., Luo, J. R., Gao, F., Yan, Y., Chen, L., Morris, J. C., & Crane, P. K. (2013) · Statistics in Biopharmaceutical Research · doi:10.1080/19466315.2012.756662 · Cited by 15
“…that, although the immunization resulted in clearance of amyloid plaques in the brain, this clearance did not prevent progressive neurodegeneration (Holmes et al. 2008), suggesting that it may be too late for such treatments to have an effect when given to persons with diagnosed AD (St…”
BackgroundBrains for Dementia Research: The Importance of Cohorts in Brain Banking
Francis, P. T., Hayes, G. M., Costello, H., & Whitfield, D. (2019) · Neuroscience Bulletin · doi:10.1007/s12264-018-0327-2 · Cited by 16
“Such tissue continues to provide important contributions to in vivo imaging of Ab [8] and the effect of disease-modifying treatments such as vaccination against Ab [9].”
Shi, M., Chu, F., Tian, X., Aerqin, Q., Zhu, F., & Zhu, J. (2021) · The Neuroscientist · doi:10.1177/1073858420987224 · Cited by 14
Fighting fire with fire: The immune system might be key in our fight against Alzheimer’s disease
Dujardin, P., Vandenbroucke, R. E., & Hoecke, L. V. (2022) · Drug Discovery Today · doi:10.1016/j.drudis.2022.01.004 · Cited by 14
Probiotic supplement as a promising strategy in early tau pathology prevention: Focusing on GSK-3β?
Flynn, C. M., & Yuan, Q. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1159314 · Cited by 15
“Therapeutics that are successful in removing Aβ plaques have failed in improving cognitive function (Holmes et al., 2008; Tayeb et al., 2013).”
BackgroundRegulation of β cleavage of amyloid precursor protein
Wang, J., Lu, R., & Wang, Y.-Z. (2010) · Neuroscience Bulletin · doi:10.1007/s12264-010-0515-1 · Cited by 14
Winkler, D. T., Abramowski, D., Danner, S., Zurini, M. G. M., Paganetti, P., Tolnay, M., & Staufenbiel, M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.01.030 · Cited by 14
Glaucoma and Alzheimer’s Disease in the Elderly
Bizrah, M., Guo, L., & Cordeiro, M. F. (2011) · Aging Health · doi:10.2217/ahe.11.51 · Cited by 14
Qin, H., Lim, L., Wei, Y., Gupta, G., & Song, J. (2013) · F1000Research · doi:10.12688/f1000research.2-221.v1 · Cited by 14
“Paradoxically, recent studies have suggested that the accumulation of aggregates is unlikely to be the first step in pathogenesis 7–9 .”
Amyloid and immune homeostasis
Wang, Y., & Zhang, Y.-G. (2017) · Immunobiology · doi:10.1016/j.imbio.2017.10.038 · Cited by 14
Ma, X., Li, J., Cui, X., Li, F., & Wang, Z. (2019) · Journal of Functional Foods · doi:10.1016/j.jff.2019.01.002 · Cited by 14
Immunotherapy for the treatment of Alzheimer's disease: amyloid-β or tau, which is the right target?
Kayed, R., Castillo‐Carranza, D. L., & Guerrero‐Munoz, M. J. (2013) · ImmunoTargets and Therapy · doi:10.2147/itt.s40131 · Cited by 16
Qin, H., Lim, L., Wei, Y., Gupta, G., & Song, J. (2014) · F1000Research · doi:10.12688/f1000research.2-221.v2 · Cited by 13
Active immunotherapy and alternative therapeutic modalities for Alzheimer's disease
Weninger, S. C., Sperling, B., Alexander, R., Ivarsson, M., Menzies, F. M., Powchik, P., Weber, C. J., Altar, C. A., Crystal, R. G., Haggarty, S. J., et al. (2020) · Alzheimer s & Dementia Translational Research & Clinical Interventions · doi:10.1002/trc2.12090 · Cited by 13
Jia, F., Chibhabha, F., Yang, Y., Kuang, Y., Zhang, Q., Ullah, S., Liang, Z., Xie, M., & Li, F. (2020) · Journal of Materials Chemistry B · doi:10.1039/d0tb02320e · Cited by 13
Götz, J., Richter-Stretton, G. L., & Cruz, E. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13071002 · Cited by 15
“In this context, it is important to note that deposition of Aβ in the brain is not sufficient to develop dementia, and similarly, removing the peptide in patients with AD by itself is not sufficient to restore their cognitive functions [29].”
BackgroundGene Expression Analysis of the Endocannabinoid System in Presymptomatic APP/PS1 Mice
Vidal-Palencia, L., Ramon‐Duaso, C., González-Parra, J. A., & Busquets-García, A. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.864591 · Cited by 16
Translational Research in Neurology
Honig, L. S. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.2883 · Cited by 13
Machida, K., Tsuchiya‐Suzuki, A., Sano, K., Arima, K., Saito, Y., Kametani, F., & Ikeda, S. (2012) · Amyloid · doi:10.3109/13506129.2011.648288 · Cited by 14
Novel Pharmacotherapies for Alzheimer's Disease
Han, S. (2009) · Journal of Korean Medical Association · doi:10.5124/jkma.2009.52.11.1059 · Cited by 11
Could immunomodulation be used to prevent prion diseases?
Wısnıewskı, T., & Goñi, F. (2012) · Expert Review of Anti-infective Therapy · doi:10.1586/eri.11.177 · Cited by 13
Active Immunotherapy to Prevent Alzheimer Disease—A DNA Amyloid β 1-42 Trimer Vaccine
Rosenberg, R. N., & Lambracht‐Washington, D. (2019) · JAMA Neurology · doi:10.1001/jamaneurol.2019.4182 · Cited by 13
Hunter, S., Friedland, R. P., & Brayne, C. (2010) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2009.00117.x · Cited by 13
“publishing of the trial showing removal of Aβ in patients but with no improvement in cognition [44] and mouse studies showing presenilin but not Aβ dependent cognitive impairment [45–47], the cascade hypothesis has been brought into question.”
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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