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 amyloid-beta in cerebrospinal fluid or the hippocampus increases after sleep deprivation or slow-wave sleep disruption.
“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]
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.
“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]
Recent clinical trials attempting to replicate benefits of Aβ immunotherapy seen in mouse models have been primarily unsuccessful in preventing early cognitive decline in AD patients despite significantly decreasing amyloid burden.
“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
Subsequent clinical analyses of the Aβ vaccine trial were at best unimpressive.
“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]
Anti-Aβ immunotherapy in individuals with mid- to late-stage clinical AD partially cleared AβPs, but this clearance did not seem to mitigate NFT formation or the inexorable disease course.
“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]
Lesion turnover (i.e. AβPs being possibly reabsorbed during life so that they would not be 'counted' at autopsy) seems to occur in some subjects.
“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]
Aβ vaccine trials attest to the ability of the immune system to clear diffuse AβPs.
“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]
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.
“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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“This is key for the successful outcome of current immunization trials against Aβ in which plaques are solubilized, but Aβ becomes entrapped in the IPAD pathways, increasing the severity of CAA and most likely resulting in amyloid-related imaging abnormalities (Holmes et al., 2008; Sperling et al., 2012; Weller et al.,…”
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Exercise, cognitive function, and aging
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“decline in people with a clinical diagnosis of early AD [67].”
- 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
- Health Sciences › Medicine › Physiology › 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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