Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report
Abstract
Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9).
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Defects in the phagocytic function of microglia can be restored with Aβ immunization and anti-inflammatory drug treatment.
“However, several studies have shown that defects in the phagocytic function of microglia can be restored with Aβ immunization [18, 23] and anti-inflammatory drug treatment [24, 25].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [23]
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 [271]
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- Authors
- Nicoll, J. A. R., Wilkinson, D., Holmes, C., Steart, P., Markham, H., & Weller, R. O.
- Affiliations
- Southampton General Hospital (GB)
- Moorgreen Hospital (GB)
- Corresponding author
- Nicoll, James A.R.
- Venue
- Nature Medicine
- Published
- 2003-03-17
- Volume
- 9
- Issue
- 4
- Pages
- 448-452
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2000917982
- Cited by
- 1,397
- References
- 14
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 24 · 2023: 24 · 2022: 32 · 2021: 32 · 2020: 32 · 2019: 41 · 2018: 25 · 2017: 39 · 2016: 46 · 2015: 48 · 2014: 68 · 2013: 70 · 2012: 58
- FWCI
- 72.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, amyloid-beta immunotherapy, amyloid-beta, neuropathology, amyloid plaques, cerebral amyloid angiopathy, neurofibrillary tangles, neuropil threads, microglia, macrophage infiltration, plaque clearance
- MeSH terms
- Aged, Alzheimer Disease, Brain, Female, Humans, Meningoencephalitis, Peptide Fragments, Amyloid beta-Peptides, Alzheimer Vaccines
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