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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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Is passive immunization for Alzheimer's disease ‘alive and well’ or ‘dead and buried’?
Jicha, G. A. (2009) · Expert Opinion on Biological Therapy · doi:10.1517/14712590902828285 · Cited by 40
“[20,28,29]Irrespective of meningoencephalitis, the autopsied cases demonstrated significantly less Aβ deposition compared to control AD cases.[23,26,28]Despite a decreased Aβ load in these subjects, the majority (7/8) subjects in a recent series developed end stage clinical disease in a similar time frame expected for…”
BackgroundResultTransglutaminase Activation in Neurodegenerative Diseases
Jeitner, T. M., Muma, N. A., Battaile, K. P., & Cooper, A. J. L. (2009) · Future Neurology · doi:10.2217/fnl.09.17 · Cited by 38
Activation of Protein Kinase C Isozymes for the Treatment of Dementias
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“Importantly, case reports suggested that anti-Ab42 antibodies were not responsible for the central nervous system (CNS) inflammation [10], while significantly reducing the amyloid-plaque load [11,12].”
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Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection
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“The concentrations of Ab40 and Ab42 were measured using Human Ab(1-40) ELISA kit and Human Ab(1-42) ELISA kit (both purchased from IBL, Japan) according to the manufacturer’s instructions.”
MethodSystemic and Central Immunity in Alzheimer's Disease: Therapeutic Implications
Butchart, J., & Holmes, C. (2011) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2011.00245.x · Cited by 36
“Microglia contained Aβ particles, implying phagocytosis as the method of clearance [165] and furthermore, the degree of plaque removal was associated with mean antibody response [166].”
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Three Postulates to Help Identify the Cause of Alzheimer's Disease
de la Torre, J. C. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101884 · Cited by 39
“Recent studies of people treated with immunization against A 42 revealed that, despite virtual clearance of A plaques from AD brains, no cognitive improvement nor prevention of progressive neurodegeneration was evident [21].”
Amyloid beta peptide immunotherapy in Alzheimer disease
Delrieu, J., Ousset, P., Voisin, T., & Vellas, B. J. (2014) · Revue Neurologique · doi:10.1016/j.neurol.2014.10.003 · Cited by 35
Biomarkers and cognitive endpoints to optimize trials in Alzheimer's disease
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“Recent studies indicate a limited performance of these therapeutic candidates in patients with clinically overt dementia (Holmes et al. 2008; Lannfelt et al. 2008).”
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“One study, in which AD patients were actively immunized with Aβ42, reported clearance of amyloid plaques but no improvement in time to severe dementia or survival [4].”
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“In addition, pathological studies of patients receiving active immunization with Aβ peptide who did not reveal side effects, such as severe encephalitis, revealed clearance of Aβ in the brain, while the clinical records of such patients did not support improvement of the symptoms.(6) The results of three clinical Phas…”
ResultNew insights in drug development for Alzheimer's disease based on microglia function
Qiao, O., Ji, H., Zhang, Y., Zhang, X., Zhang, X., Liu, N., Huang, L., Liu, C., & Gao, W. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.111703 · Cited by 35
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“However, this did not prevent the progressive cognitive decline [3,4].”
Butyrylcholinesterase genotype and gender influence Alzheimer's disease phenotype
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“However, despite the observation that microglia can clear plaques after Ab immunization, there is limited evidence of benefit of Ab immunotherapy, in terms of reductions in tau pathology, brain volume loss, or symptomatic decline, in established AD [403].”
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“Diagnosis of the first AD patient, back in 1906, revealed large numbers of SP and NFT; however, although new treatments aimed at reversing the disease by reducing SP have proven successful, they have been without improvements in cognitive abilities of patients [35].”
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“In the first active immunization trial, AN1792, clearance of Aβ plaques from the brain did not appear to slow the progression of dementia (Holmes et al. 2008).”
Takamura, A., Okamoto, Y., Kawarabayashi, T., Yokoseki, T., Shibata, M. S., Mouri, A., Nabeshima, T., Sun, H., Abe, K., Urisu, T., et al. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-20 · Cited by 34
A refined concept: α-synuclein dysregulation disease
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“nificant benefits in cognition despite a reduction in Ab plaques of AD patients (Holmes et al., 2008).”
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The Mitochondrial Secret(ase) of Alzheimer's Disease
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“Antibodies generated against A in the human vaccine trials were composed almost exclusively of N-terminal anti-A antibodies, yet ultimately the serum cleared both intact and N-terminally truncated A (although the latter was cleared more slowly) (Holmes et al., 2008).”
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Humanin; A Defender Against Alzheimers Disease?
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Tobinick, E. L. (2012) · Current Alzheimer Research · doi:10.2174/156720512799015073 · Cited by 34
“Removal of amyloid plaque via active immunization, even when successful, did not alter the trajectory of decline into severe dementia [11,12].”
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Are Aβ and Its Derivatives Causative Agents or Innocent Bystanders in AD?
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“expressed by these animals. Finally, recent studies in humans showed that clearance of amyloid depositions resulted neither in cognitive improvement nor in decreased rate of mental deterioration [”
ResultWhy therapies for Alzheimer’s disease do not work: Do we have consensus over the path to follow?
Amtul, Z. (2015) · Ageing Research Reviews · doi:10.1016/j.arr.2015.09.003 · Cited by 35
Alzheimer’s Disease: Current Status of Etiopathogenesis and Therapeutic Strategies
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“, 2007), as well as from the AN-1792 trial (Holmes et al., 2008; Patton et al., 2006; St George-Hyslop and Morris, 2008) that early preventive immunization prior to substantial neuropathology, neuronal loss, and cognitive deficits have become firmly established may be more effective and safer for future patients recei…”
BackgroundInfluentialImmunology meets neuroscience – Opportunities for immune intervention in neurodegenerative diseases
Lynch, M. A., & Mills, K. H. G. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.05.013 · Cited by 34
TL-2 attenuates β-amyloid induced neuronal apoptosis through the AKT/GSK-3β/β-catenin pathway
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“Although immunization with Aβ42 does not prevent the progressive neurodegeneration in patients with AD (Holmes et al., 2008), it is generally considered that accumulation of Aβ is the key event in AD pathology and contributes to neuronal cell death and the formation of NFTs (Karran et al., 2011;…”
Revisiting nicotine’s role in the ageing brain and cognitive impairment
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“…have shown that administration of anti-A β antibody injection reduces cognitive impairments in these animals (Kumar et al., 2000; Banks et al., 2001), although recent clinical trials with similar antibodies have failed to show disease-modifying benefits in patients with AD (Holmes et al., 2008).”
Satou, T., Hanashima, Y., Mizutani, I., & Koike, K. (2018) · Flavour and Fragrance Journal · doi:10.1002/ffj.3435 · Cited by 33
Clinical trials of prion disease therapeutics
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Severini, C., Barbato, C., Certo, M. G. D., Gabanella, F., Petrella, C., Stadio, A. D., VINCENTIIS, M. D., Polimeni, A., Ralli, M., & Greco, A. (2020) · Current Neuropharmacology · doi:10.2174/1570159x18666200621204546 · Cited by 34
Amyloids: The History of Toxicity and Functionality
Yakupova, E. I., Bobyleva, L. G., Shumeyko, S. A., Vikhlyantsev, I. M., & Bobylev, A. G. (2021) · Biology · doi:10.3390/biology10050394 · Cited by 34
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Advances in the development of kinase inhibitor therapeutics for Alzheimer's disease
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“The need to expand therapeutic approaches for AD beyond amyloid targets is evident as recent clinical trial results question the efficacy of this approach [Wilcock et al., 2008; Fagan 2008; Holmes et al., 2008; McCaffrey and Strobel, 2007; Strobel, 2008].”
The Amyloid Cascade Hypothesis
Castellani, R. J., Jamshidi, P., Plascencia‐Villa, G., & Perry, G. L. (2024) · American Journal Of Pathology · doi:10.1016/j.ajpath.2024.10.014 · Cited by 39
Current and Emerging Therapies for Alzheimer’s Disease
Nygaard, H. B. (2013) · Clinical Therapeutics · doi:10.1016/j.clinthera.2013.09.009 · Cited by 32
Interpreting Alzheimer’s disease clinical trials in light of the effects on amyloid-β
Toyn, J. H., & Ahlijanian, M. K. (2014) · Alzheimer s Research & Therapy · doi:10.1186/alzrt244 · Cited by 31
“However, it remains unclear to what extent such proximal, plaque-associated dysfunction contributes to the global cognitive impairment observed in AD patients, particularly since cognitive function did not improve in a small number of patients with reduced plaque after treatment with AN1792 [93,94].”
BackgroundWang, H., Liu, X., Chen, S., & Ye, K. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1815915115 · Cited by 32
Pathogenic Feed-Forward Mechanisms in Alzheimer’s and Parkinson’s Disease Converge on GSK-3
Albeely, A. M., Ryan, S. D., & Perreault, M. L. (2018) · Brain Plasticity · doi:10.3233/bpl-180078 · Cited by 33
“Importantly, even with the successful elimination of A in AD there is still question as to whether this will result in a cure as one study showed that the clearance of A plaques via A 42 immunization did not prevent progressive neurodegeneration in AD patients [145].”
ResultRecent advances of induced pluripotent stem cells application in neurodegenerative diseases
Amin, N., Tan, X., Ren, Q., Zhu, N., Botchway, B. O. A., Hu, Z., & Fang, M. (2019) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2019.109674 · Cited by 36
Animal Models of Parkinson’s Disease: Are They Useful or Not?
Barker, R., & Björklund, A. (2020) · Journal of Parkinson's Disease · doi:10.3233/jpd-202200 · Cited by 31
Stojakovic, A., Chang, S.-Y., Nesbitt, J. J., Pichurin, N. P., Ostroot, M., Aikawa, T., Kanekiyo, T., & Trushina, E. V. (2020) · Journal of Alzheimer s Disease · doi:10.3233/jad-201015 · Cited by 31
“[3], and the reduction of amyloid plaque load in the brain after immunotherapy did not result in cognitive improvement in AD patients [4].”
BackgroundDecourt, B., Noorda, K., Noorda, K. J., Shi, J., & Sabbagh, M. N. (2022) · Journal of Experimental Pharmacology · doi:10.2147/jep.s265626 · Cited by 33
“Postmortem brain samples from the participants were then neuropathologically examined and the percentage of plaque formation was assessed to determine effectiveness.(89) It was found that, 6 years after immunization, study subjects who had died in the years following AN1792 administration (N = 7) had fewer brain Aβ ag…”
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“Alzheimer's disease (AD) is a degenerative neurological disease clinically characterised by progressive cognitive dysfunction (Holmes et al., 2008; Mattson, 2004; Stokin et al., 2005).”
BackgroundAlzheimer’s Disease: Future Treatments
Morley, J. E. (2010) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2010.10.008 · Cited by 31
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Scharfman, H. E., Kanner, A. M., Friedman, A., Blümcke, I., Crocker, C. E., Cendes, F., Diaz-Arrastia, R. R., Förstl, H., Fenton, A. A., Grace, A. A., et al. (2017) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2017.09.016 · Cited by 31
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“, 2016); the latter may explain why Aβ-targeted therapies have generally proven ineffective at halting disease progression in subjects with mild cognitive impairment (MCI), a precursor of early-to-moderate AD (Holmes et al., 2008).”
BackgroundHermann, D. J., Mezler, M., Müller, M., Wicke, K. M., Groß, G., Draguhn, A., Bruehl, C., & Nimmrich, V. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.01.030 · Cited by 31
Cognitive impairment in the Tg6590 transgenic rat model of Alzheimer’s disease
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“However, follow-up of a phase I trial of immunization with Ab42 did not prevent clinical progression of dementia, tauopathy, or neuronal cell loss, even though it resulted in the clearance of amyloid plaques (Holmes et al., 2008).”
BackgroundRationale for Peptide and DNA Based Epitope Vaccines for Alzheimers Disease Immunotherapy
Ghochikyan, A. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787847298 · Cited by 32
“However a recent assessment of the relationship between Aβ42 immune response, degree of plaque removal and long-term clinical outcomes demonstrated that clearance of amyloid plaques in the brains of AD patients is not accompanied by the prevention of progressive neurodegeneration [32].”
BackgroundLambracht‐Washington, D., Qu, B., Fu, M., Anderson, L. D., Eagar, T. N., Stüve, O., & Rosenberg, R. N. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.09.008 · Cited by 33
“…active Aβ1–42 immunization in AD patients (AN1792) has lead to the conclusion that the antibody response was beneficial but the accompanying inflammatory Th1 T cell response was harmful and was responsible for the meningoencephalitis in 6% of the patients (Gilman et al. 2005, Holmes et al, 2008).”
BackgroundBoon, B. D. C., Piura, Y. D., Moloney, C. M., Chalk, J. L., Lincoln, S., Rutledge, M. H., Rothberg, D. M., Kouri, N., Hinkle, K. M., Roemer, S. F., et al. (2025) · The Lancet Neurology · doi:10.1016/s1474-4422(25)00313-8 · Cited by 37
Refinement of a DNA based Alzheimer disease epitope vaccine in rabbits
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Is Alzheimer's disease amyloidosis the result of a repair mechanism gone astray?
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“[4] Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al.”
BackgroundPotential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Tanaka, M., Saitô, S., Inoue, T., Satoh‐Asahara, N., & Ihara, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21061992 · Cited by 31
“Other drugs based on anti-Aβ immunotherapy reduced brain Aβ plaques, but did not result in cognitive benefits [13,14].”
BackgroundKabir, M. T., Uddin, M. S., Mathew, B., Das, P. K., Perveen, A., & Ashraf, G. M. (2020) · Current Topics in Medicinal Chemistry · doi:10.2174/1568026620666200422105156 · Cited by 32
Blood-Based Protein Biomarkers for Diagnosis and Classification of Neurodegenerative Diseases
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Innate immunity in Alzheimer’s disease: the relevance of animal models?
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“A long-term clinical-neuropathological follow-up of the patients showed continued cognitive decline despite clearance in amyloid plaques in some patients (Holmes et al. 2008).”
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Alzheimer's disease: on the verges of treatment and prevention
Burns, A. S. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70271-0 · Cited by 30
Flavonoids and Alzheimer’s disease: reviewing the evidence for neuroprotective potential
Amin, M. A., Dehbia, Z., Nafady, M. H., Zehravi, M., Kumar, K. P., Haque, M. A., Baig, M. S., Farhana, A., Khan, S. L., Afroz, T., et al. (2024) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-023-04922-w · Cited by 29
“ELAN’s initial active AD vaccine (AN1792) showed benefits in reducing cognitive deterioration but was halted due to unfavorable outcomes like meningoencephalitis [90].”
Fluid Biomarkers in Clinical Trials of Alzheimer’s Disease Therapeutics
Ritter, A. R., & Cummings, J. L. (2015) · Frontiers in Neurology · doi:10.3389/fneur.2015.00186 · Cited by 29
“Nonetheless, several interesting findings have been reported including reductions in plaque load (174) and decreased microglial activation (173).”
BackgroundNeuroimaging of dementia in 2013: what radiologists need to know
Haller, S., Garibotto, V., Kövari, E., Bouras, C., Xekardaki, A., Rodriguez, C. K., Lazarczyk, M. J., Giannakopoulos, P., & Lövblad, K. (2013) · European Radiology · doi:10.1007/s00330-013-2957-0 · Cited by 30
“Early treatment is probably more beneficial in stopping or at least slowing down the progressive neurodegeneration than treatment of clinically overt dementia at a late stage [60, 61].”
BackgroundTeipel, S. J., Buchert, R., Thome, J., Hampel, H. J., & Pahnke, J. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2011.05.004 · Cited by 31
“The visualization of amyloid-plaque load in vivo is considered as one of the most relevant lines of investigation for translational applications in human studies, despite the controversial findings in the human immunization studies (Holmes et al., 2008; Pahnke et al., 2009).”
Brain Aging and Late-Onset Alzheimer’s Disease: A Matter of Increased Amyloid or Reduced Energy?
Mecocci, P., Baroni, M., Senin, U., & Boccardi, V. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179903 · Cited by 30
Aβ43 in human Alzheimer’s disease: effects of active Aβ42 immunization
Jäkel, L., Boche, D., Nicoll, J. A. R., & Verbeek, M. M. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0791-6 · Cited by 29
“brain, although so far the effects on slowing or preventing cognitive decline have been mainly disappointing [12, 31, 35].”
BackgroundResultSelf-citationShared pathophysiology: Understanding stroke and Alzheimer’s disease
Sriram, S., Mehkri, Y., Quintin, S. S., & Lucke-Wold, B. P. (2022) · Clinical Neurology and Neurosurgery · doi:10.1016/j.clineuro.2022.107306 · Cited by 29
Why Alzheimer's Disease Starts with a Memory Impairment: Neurophysiological Insight
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“Another trial also showed no effect of A β immunotherapy on cognitive performance and survival of AD patients, despite evidence of a reduction in A β deposits and plaque removal [177].”
Froestl, W., Pfeifer, A., & Muhs, A. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121729 · Cited by 27
“The scientific harvest of this single clinical trial is listed in chronological order [1254–1286] (Thomson Reuters Pharma, update of August 24, 2012).”
BackgroundTransgenic Rice Expressing Amyloid β-peptide for Oral Immunization
Yoshida, T., Kimura, E., Koike, S., Nojima, J., Futai, E., Sasagawa, N., Watanabe, Y., & Ishiura, S. (2011) · International Journal of Biological Sciences · doi:10.7150/ijbs.7.301 · Cited by 29
“In a 6-year follow-up of patients in the trial of AD immunization [9], cortical Aβ loads were lower in immunized patients compared to the control group.”
BackgroundZhou, J.-B., Zheng, Y., Zeng, Y., Wang, J., Pei, Z., & Pang, J. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.02.028 · Cited by 29
Prevention of age-associated dementia
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“reported later that although AN1792 immunization resulted in clearance of Ab plaques, this clearance did not prevent progressive neurodegeneration [10].”
BackgroundOvercoming translational barriers impeding development of Alzheimer's disease modifying therapies
Golde, T. E. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13583 · Cited by 29
“Although one might infer from the AN1792 that active immunization can clear ‘amyloid’ and clearly did not alter clinical outcomes, the AN1792 data are based on much too small of sample set with no longitudinal imaging data and are, therefore, too anecdotal to have any predictive value (Holmes et al. 2008).”
BackgroundAntibody-based therapies for Huntington’s disease: current status and future directions
Denis, H. L., David, L. S., & Cicchetti, F. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104569 · Cited by 33
“%) mounted a significant antibody response (Lee et al., 2005b) and that there were no measurable cognitive improvements (Holmes et al., 2008; Nicoll et al., 2003), post-mortem evaluation revealed that patients had markedly less amyloid plaques (Boche et al., 2010).”
BackgroundTownsend, D. J., Mala, B., Hughes, E., Hussain, R., Siligardi, G., Fullwood, N. J., & Middleton, D. A. (2020) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.0c00154 · Cited by 27
PEG-Ceramide Nanomicelles Induce Autophagy and Degrade Tau Proteins in N2a Cells
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The Impact of Ageing on the CNS Immune Response in Alzheimer’s Disease
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“Post-mortem neuropathological examination of a group of AN1792 immunised AD patients verified clearance of amyloid plaques; however, this clearance did not prevent progressive neurodegeneration [39].”
BackgroundImmunotherapy in Alzheimer's Disease: Where Do We Stand? Where Should We Go?
Rommy von Bernhardi, M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-1248 · Cited by 28
Autoreactive‐Aβ antibodies promote APP β‐secretase processing
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“In patients vaccinated against the N-terminus of Ab, considerable decreases in plaque load have been reported, but this clearance of pre-formed plaques was not sufficient to improve cognitive function in AD patients (Holmes et al. 2008).”
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“removal did not prevent progressive neurodegeneration[17].”
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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