The DOI matches its Crossref record; 131 of the 132 references it cites were found in a registry or an index.
Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer’s disease pathogenesis
Abstract
The amyloid cascade hypothesis of Alzheimer's disease (AD) is testable: it implies that interference with Abeta aggregation and plaque formation may be therapeutically useful. Abeta42 immunisation of amyloid precursor protein (APP) transgenic mice prevented plaque formation and caused removal of existing plaques. The first clinical studies of Abeta immunisation in AD patients (AN1792, Elan Pharmaceuticals) were halted when some patients suffered side effects. Since our confirmation that Abeta immunisation can prompt plaque removal in human AD, we have performed a clinical and neuropathological follow up of AD patients in the initial Elan Abeta immunisation trial. In immunised AD patients, we found: a lower Abeta load, with evidence that plaques had been removed; a reduced tau load in neuronal processes, but not in cell bodies; and no evidence of a beneficial effect on synapses. There were pathological "side effects" including: increased microglial activation; increased cerebral amyloid angiopathy; and there is some evidence for increased soluble/oligomeric Abeta. A pathophysiological mechanism involving effects on the cerebral vasculature is proposed for the clinical side effects observed with some active and passive vaccine protocols. Our current knowledge of the effects of Abeta immunotherapy is based on functional information from the early clinical trials and a few post mortem cases. Several further clinical studies are underway using a variety of protocols and important clinical, imaging and neuropathological data will become available in the near future. The information obtained will be important in helping to understand the pathogenesis not only of AD but also of other neurodegenerative disorders associated with protein aggregation.
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“There is also evidence that amyloid removal is faster in those patients with high baseline levels, further confounding a direct comparison of anti-Aβ antibodies 90 .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“| Gantenerumab | 13 1 | 42 b /27 | 67 | 52 | 2.5 | 48 b | 19.2 |”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [90]
In the citing paper
“In one human study, a vaccine to Aβ did reduce plaque burden, a remarkable technical achievement [248, 249].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [248]
In the citing paper
“In the first active immunization trial, the AN-1792 vaccine seemed to show some ability to clear Aβ plaque-associated tau lesions through plaque removal179–181”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [180]
In the citing paper
“There are multiple reasons why these trials may have failed, including the late timing of the therapy. Thus, conclusions drawn from these trials may be premature (72, 73).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [72]
Citations
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Research works printed but not linked: 1
- Oh JY, Nam YJ, Jo A et al (2010) Apolipoprotein (APOE) mRNA is transported to dendrites and may have a role in synaptic structural plasticity. J Neurochem [Epub ahead of print] 2010 April 28. doi: 10.1111/j.1471-4159.2010.06773 · DOI
Cited by
Sorted by citations
The neuropathological diagnosis of Alzheimer's disease
DeTure, M. A., & Dickson, D. W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0333-5 · Cited by 3,329
“Interestingly, immunization strategies targeting Aβ peptides may be useful in alleviating amyloid plaque burden, while shifting amyloid into CAA, sometimes associated with inflammation and hemorrhage [51, 52].”
BackgroundNelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050
Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease
Prinz, M., & Priller, J. (2014) · Nature Reviews Neuroscience · doi:10.1038/nrn3722 · Cited by 1,329
Microglial priming in neurodegenerative disease
Perry, V. H., & Holmes, C. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.38 · Cited by 1,127
Self-citationTau-targeting therapies for Alzheimer disease
Congdon, E. E., & Sigurdsson, E. M. (2018) · Nature Reviews Neurology · doi:10.1038/s41582-018-0013-z · Cited by 1,113
Metadata
- Authors
- Boche, D., Denham, N., Holmes, C., & Nicoll, J. A. R.
- Affiliations
- Southampton General Hospital (GB)
- Corresponding author
- Boche, Delphine
- Venue
- Acta Neuropathologica
- Published
- 2010-07-15
- Volume
- 120
- Issue
- 3
- Pages
- 369-384
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- OpenAlex
- W2077023014
- Cited by
- 135
- References
- 132
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 1 · 2023: 3 · 2022: 8 · 2021: 1 · 2020: 8 · 2019: 12 · 2018: 4 · 2017: 5 · 2016: 8 · 2015: 5 · 2014: 15 · 2013: 19 · 2012: 15
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- 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-beta immunotherapy, amyloid-beta 42, amyloid hypothesis, amyloid plaques, tau pathology, microglial activation, cerebral amyloid angiopathy, cerebral vasculature, vaccine side effects, amyloid precursor protein transgenic mice, Alzheimer's disease pathogenesis
- MeSH terms
- Alzheimer Disease, Animals, Brain, Clinical Trials as Topic, Humans, Peptide Fragments, Amyloid beta-Peptides, Immunotherapy, Active, Alzheimer Vaccines, Mice
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