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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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Unbiased comparison of sample size estimates from longitudinal structural measures in ADNI
Holland, D., McEvoy, L. K., Dale, A. M., & Initiative, T. A. D. N. (2011) · Human Brain Mapping · doi:10.1002/hbm.21386 · Cited by 85
“…clinical improvement in this trial largely may have been precluded because the patient cohort was at a relatively advanced stage of the disease [Holmes et al., 2008; Hyman, 2011], this outcome nevertheless argues in favor of analyzing subregional, in particular cortical, change rather than…”
ResultRyan, P., Xu, M., Davey, A. K., Danon, J. J., Mellick, G. D., Kassiou, M., & Rudrawar, S. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.9b00143 · Cited by 84
Callaway, J. K., Jones, N. C., Royse, A. G., & Royse, C. F. (2012) · Anesthesiology · doi:10.1097/aln.0b013e31826cb228 · Cited by 84
Clark, I. A., & Vissel, B. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13181 · Cited by 84
Developing novel immunogens for a safe and effective Alzheimer's disease vaccine
Lemere, C. A. (2009) · Progress in brain research · doi:10.1016/s0079-6123(09)17506-4 · Cited by 83
“In most of the patients who have come to autopsy since the initiation of the trial, plaque deposition was focally and regionally reduced (Nicoll et al., 2003, 2006; Ferrer et al., 2004; Masliah et al., 2005; Holmes et al., 2008).”
Backgroundβ-amyloid oligomers and cellular prion protein in Alzheimer’s disease
Gunther, E. C., & Strittmatter, S. M. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0568-7 · Cited by 84
“It has been observed that among AD patients actively immunized with Aβ, some individuals had few plaques but severe end-stage dementia before death [6].”
Fisher, Y., Nemirovsky, A., Baron, R., & Monsonego, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0010830 · Cited by 83
Two decades of new drug discovery and development for Alzheimer's disease
Liu, Z., Zhang, A., Sun, H. J., Han, Y., Kong, L. D., & Wang, X. (2017) · RSC Advances · doi:10.1039/c6ra26737h · Cited by 84
Yuan, S.-M., Gao, K., Wang, D., Quan, X., Liu, J., Ma, C., Qin, C., & Zhang, L. (2011) · Acta Pharmacologica Sinica · doi:10.1038/aps.2010.230 · Cited by 82
Denver, P., & McClean, P. L. (2018) · Neural Regeneration Research · doi:10.4103/1673-5374.238608 · Cited by 89
“…independently of effects on Aβ (Ko-tilinek et al., 2002; Hock et al., 2003; Chen et al., 2007) and reductions of Aβ pathology don’t always correlate with improved cognition, nor does reducing amyloid burden always slow progression of neurodegeneration (Holmes et al., 2008; Kokjohn and Roher, 2009).”
BackgroundCaselli, R. J., Beach, T. G., Knopman, D. S., & Graff-Radford, N. R. (2017) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2017.02.011 · Cited by 81
Microvascular Alterations in Alzheimer's Disease
Steinman, J., Sun, H., & Feng, Z. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.618986 · Cited by 85
“Some patients demonstrated signs of severe dementia despite clearance of amyloid deposits (Holmes et al., 2008; Gallardo and Holtzman, 2017).”
BackgroundAmyloid-β Peptide and Oligomers in the Brain and Cerebrospinal Fluid of Aged Canines
Head, E., Pop, V., Sarsoza, F. M., Kayed, R., Beckett, T. L., Studzinski, C. M., Tomic, J. L., Glabe, C. G., & Murphy, M. P. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1397 · Cited by 84
“In this regard it is worth noting that immunization with fibrillar A β in aged canines may be a better parallel to human trials with this therapeutic approach than preclinical mouse models [34,35].”
Oleuropein aglycone counteracts Aβ42 toxicity in the rat brain
Luccarini, I., Dami, T. E., Grossi, C., Rigacci, S., Stefani, M., & Casamenti, F. (2013) · Neuroscience Letters · doi:10.1016/j.neulet.2013.10.062 · Cited by 81
Alzheimer’s and ABC transporters — new opportunities for diagnostics and treatment
Pahnke, J., Langer, O., & Krohn, M. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.04.001 · Cited by 84
Murine models of Alzheimer's disease and their use in developing immunotherapies
Wısnıewskı, T., & Sigurdsson, E. M. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.05.004 · Cited by 84
Shahaduzzaman, M., Nash, K. R., Hudson, C., Masroor, S., Grimmig, B. A., Lin, X., Bai, G., Liu, H., Ugen, K. E., Cao, C., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116841 · Cited by 88
Loeffler, D. A. (2023) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-230025 · Cited by 90
“survival time or time to severe dementia [187].”
BackgroundREVIEW: γ‐Secretase Inhibitors for the Treatment of Alzheimer's Disease: The Current State
Panza, F., Frisardi, V., Imbimbo, B. P., Capurso, C. A., Logroscino, G., Sancarlo, D., Seripa, D., Vendemiale, G., Pilotto, A., & Solfrizzi, V. (2010) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2010.00164.x · Cited by 80
“The most recent challenge derives from a recently published article: although immunization with preaggregated Aβ42 (AN-1792; formerly in development by Elan Corp plc and Wyeth) resulted in almost complete clearance of SPs from the brain of patients with AD, plaque removal did not prevent progressive neurodegeneration…”
BackgroundSabbagh, M. N., Cooper, K., DeLange, J., Stoehr, J. D., Thind, K., Lahti, T., Reisberg, B., Sue, L., Vedders, L., Fleming, S. R., et al. (2010) · Current Alzheimer Research · doi:10.2174/156720510791162340 · Cited by 79
Sabbagh, J. J., Kinney, J. W., & Cummings, J. L. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.02.027 · Cited by 80
“However, despite almost total clearance of Aß plaques in some AD patients following Aß immunization, neurodegeneration continued unabated (Holmes et al., 2008).”
BackgroundAmyloid β Modification: A Key to the Sporadic Alzheimer's Disease?
Barykin, E. P., Mitkevich, V. A., Kozin, S. A., & Makarov, A. А. (2017) · Frontiers in Genetics · doi:10.3389/fgene.2017.00058 · Cited by 84
“The amyloid hypothesis was on the edge of being discredited due to the indistinct correlation between β-amyloid (Aβ) deposition and neuronal loss (Holmes et al., 2008; Mullane and Williams, 2013).”
BackgroundRoyea, J., Zhang, L., Tong, X., & Hamel, É. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.0329-17.2017 · Cited by 78
“Our results thus exclude a role for AT4Rs on the amyloid pathology and agree with clinical trials using active A 1-42 immunization, in which patients deteriorated cognitively despite plaque clearance (Holmes et al., 2008).”
ResultRoss, J., Sharma, S., Winston, J., Nunez, M., Bottini, G., Franceschi, M., Scarpini, E. A., Frigerio, E., Fiorentini, F., Fernández, M., et al. (2013) · Current Alzheimer Research · doi:10.2174/13892037113149990144 · Cited by 78
Innate immune system and inflammation in Alzheimer’s disease: From pathogenesis to treatment
Serpente, M., Bonsi, R., Scarpini, E., & Galimberti, D. (2014) · Neuroimmunomodulation · doi:10.1159/000356529 · Cited by 87
Alzheimer’s/Vascular Spectrum Dementia: Classification in Addition to Diagnosis
Emrani, S., Lamar, M., Price, C. C., Wasserman, V., Matusz, E. F., Au, R., Swenson, R. A., Nagele, R. G., Heilman, K. M., & Libon, D. J. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190654 · Cited by 84
Biomarkers in Amyloid-β Immunotherapy Trials in Alzheimer’s Disease
Blennow, K., Hampel, H. J., & Zetterberg, H. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.154 · Cited by 83
Autoimmune and inflammatory mechanisms of CNS damage
Kapadia, M., & Šakić, B. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.08.008 · Cited by 75
Clark, I. A., Atwood, C., Bowen, R. L., Paz-Filho, G., & Vissel, B. (2012) · Pharmacological Reviews · doi:10.1124/pr.112.005850 · Cited by 76
“Surprisingly, A plaque removal was the only mechanism considered by these authors, despite the doubt cast on the utility of this endpoint by the AD patient trial of AN1792 (A 42; Elan Pharmaceuticals, South San Francisco, CA) several years ago (Holmes et al., 2008).”
BackgroundInfluentialLa Barbera, L., Mauri, E., D’Amelio, M., & Gori, M. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.939855 · Cited by 74
“In recent times, AD research has focused on immunotherapy using MAb as alternative approach, directly targeting Aβ and leading to its clearance (Bayer et al., 2005; Gilman et al., 2005; Holmes et al., 2008; Salloway et al., 2009; Laskowitz and Kolls, 2010; La Porte et al., 2012; Burstein et al., 2013; Landen et al., 2…”
BackgroundWebster, L., Groskreutz, D., Grinbergs‐Saull, A., Howard, R. J., O'Brien, J. T., Mountain, G. A., Banerjee, S., Woods, B. T., Perneczky, R., Lafortune, L., et al. (2017) · Health Technology Assessment · doi:10.3310/hta21260 · Cited by 75
Self-citationNeuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease
Uddin, M. S., Kabir, M. T., Jalouli, M., Rahman, M. A., Jeandet, P., Behl, T., Alexiou, A. T., Albadrani, G. M., Abdel‐Daim, M. M., Perveen, A., et al. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210826130210 · Cited by 76
Vasilevko, V., Passos, G. F., Quiring, D., Head, E., Kim, R. C., Fisher, M., & Cribbs, D. H. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05786.x · Cited by 74
“Thus Anti-Aβ immunotherapy represents a potentially powerful strategy for reducing pathological forms of Aβ, and possibly aberrant forms of tau, in the brains of AD patients [98–104].”
BackgroundDisease-modifying drugs in Alzheimer's disease
Scarpini, E. A., Galimberti, D., & Ghezzi, L. (2013) · Drug Design Development and Therapy · doi:10.2147/dddt.s41431 · Cited by 74
“In 2008, a paper was published describing the relationship between Aβ42 immune response, degree of plaque removal, and long-term clinical outcomes.(40) In June 2003, 80 patients (or their caregivers), who had entered Phase I and II of the AN1792 trial, gave their consent for long-term clinical follow-up (maximum 6 yea…”
Current perspectives on pharmacotherapy of Alzheimer's disease
Chopra, K., Misra, S., & Kuhad, A. (2011) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2011.520702 · Cited by 75
“Although immunization with Ab(42) resulted in clearance of amyloid plaques in patients with Alzheimer’s disease, this clearance did not prevent progressive neurodegeneration [44].”
BackgroundBandyopadhyay, S., & Rogers, J. T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.032 · Cited by 77
“This strategy is an alternative to current amyloid targeted drugs, that while showing promise in animal models, have repeatedly failed in clinical trials [7].”
BackgroundMckean, N. E., Handley, R. R., & Snell, R. G. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313168 · Cited by 81
“Unfortunately, this approach failed to show benefits in clinical trials and 6% of the immunised patients developed meningoencephalitis [118,119].”
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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