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Amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with bapineuzumab: a retrospective analysis
Open accessAbstract
Background Amyloid-related imaging abnormalities (ARIA) have been reported in patients with Alzheimer's disease treated with bapineuzumab, a humanised monoclonal antibody against amyloid β. ARIA include MRI signal abnormalities suggestive of vasogenic oedema and sulcal effusions (ARIA-E) and microhaemorrhages and haemosiderin deposits (ARIA-H). Our aim was to investigate the incidence of ARIA during treatment with bapineuzumab, and evaluate associated risk factors.Methods Two neuroradiologists independently reviewed 2572 fluid-attenuated inversion recovery (FLAIR) MRI scans from 262 participants in two phase 2 studies of bapineuzumab and an open-label extension study. Readers were masked to the patient's treatment, APOE ɛ4 genotype, medical history, and demographics. Patients were included in risk analyses if they had no evidence of ARIA-E in their pre-treatment MRI, had received bapineuzumab, and had at least one MRI scan after treatment. We used Kaplan-Meier survival analysis to examine the distribution of incident ARIA-E from the start of bapineuzumab treatment and proportional hazards regression models to assess risk factors associated with ARIA.Findings 210 patients were included in the risk analyses. 36 patients (17%) developed ARIA-E during treatment with bapineuzumab; 15 of these ARIA-E cases (42%) had not been detected previously. 28 of these patients (78%) did not report associated symptoms. Adverse events, reported in eight symptomatic patients, included headache, confusion, and neuropsychiatric and gastrointestinal symptoms. Incident ARIA-H occurred in 17 of the patients with ARIA-E (47%), compared with seven of 177 (4%) patients without ARIA-E. 13 of the 15 patients in whom ARIA were detected in our study received additional treatment infusions while ARIA-E were present, without any associated symptoms. Occurrence of ARIA-E increased with bapineuzumab dose (hazard ratio [HR] 2·24 per 1 mg/kg increase in dose, 95% CI 1·40-3·62; p=0·0008) and presence of APOE ɛ4 alleles (HR 2·55 per allele, 95% CI 1·57-4·12; p=0·0001).Interpretation ARIA consist of a spectrum of imaging findings with variable clinical correlates, and some patients with ARIA-E remain asymptomatic even if treatment is continued. The increased risk of ARIA among APOE ɛ4 carriers, its association with high bapineuzumab dose, and its timecourse in relation to dosing suggest an association between ARIA and alterations in vascular amyloid burden.Funding Elan Corporation, Janssen Alzheimer Immunotherapy, Wyeth Pharmaceuticals, and Pfizer.
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“The main adverse effects associated with administration of certain anti-Aβ mAbs during clinical trials were amyloid related imaging abnormalities (ARIA) identified on magnetic resonance imaging (MRI) scans.”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [14]
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“However one needs to be mindful that escalation of anti-Aβ mAbs dose in APOE ε4 allele carriers may trigger increased rate of vasculotropic adverse events associated with immunization [5, 8, 14].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [14]
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“Accordingly, ApoE genotyping is now increasingly considered an important component of the pre-treatment work-up for anti-amyloid therapies [5, 8, 11, 12].”
From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [8]
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“The greater incidence of these abnormalities with increasing bapineuzumab dose and number of APOEε4 alleles is consistent with phase 2 findings.11,13”
From Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease (2014) · cites this paper as [11]
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“Some amyloid β antibodies triggered amyloid-related imaging abnormalities (ARIAs) in clinical trials and ARIAs tend to be more frequent in APOE4 carriers [28].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [28]
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“These included vasogenic edema (ARIA-E) and cerebral microhemorrhages (ARIA-H) that in about 20% of cases are associated with clinical symptoms and signs [13, 14].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [14]
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“These included vasogenic edema (ARIA-E) and cerebral microhemorrhages (ARIA-H) that in about 20% of cases are associated with clinical symptoms and signs [13, 14].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [14]
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“Frequency of ARIA events and in particular ARIA-E was significantly higher among APOE ε4 allele carriers compared to non-carriers, making the APOE ε4 allele a risk factor for vascular complications of anti-Aβ immunotherapy [5, 8, 14, 15].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [14]
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“Frequency of ARIA events and in particular ARIA-E was significantly higher among APOE ε4 allele carriers compared to non-carriers, making the APOE ε4 allele a risk factor for vascular complications of anti-Aβ immunotherapy [5, 8, 14, 15].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [14]
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“Importantly, ApoE ε4 status has gained direct clinical relevance in the anti-amyloid era”
From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [8]
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“ε4 carriers, particularly ε4 homozygotes, exhibit a substantially increased risk of amyloid-related imaging abnormalities (ARIA) during treatment with anti-amyloid monoclonal antibodies [2, 5, 8].”
From Plasma ApoE proteotyping for ApoE ε4 stratification in the anti-amyloid therapies era (2026) · cites this paper as [8]
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Metadata
- Authors
- Sperling, R., Salloway, S., Brooks, D. J., Tampieri, D., Barakos, J., Fox, N. C., Raskind, M., Sabbagh, M., Honig, L. S., Porsteinsson, A. P., Lieberburg, I., Arrighi, H. M., Morris, K. A., Lu, Y., Liu, E., Gregg, K. M., Brashear, H. R., Kinney, G. G., Black, R., & Grundman, M.
- Affiliations
- Brigham and Women's Hospital (US)
- Butler Hospital (US)
- Imperial College London (GB)
- McGill University (CA)
- California Pacific Medical Center (US)
- UCL Queen Square Institute of Neurology (GB)
- Columbia University (US)
- University of Rochester Medicine (US)
- University of California, San Francisco (US)
- Janssen Alzheimer Immunotherapy Research & Development (United States) (US)
- Corresponding author
- Sperling, Reisa
- ORCID
- Venue
- The Lancet Neurology
- Publisher
- Elsevier BV
- Published
- 2012-03
- Volume
- 11
- Issue
- 3
- Pages
- 241-249
- ISSN
- 1474-4422 (ISSN-L)
- PMC
- PMC4063417
- OpenAlex
- W2122843800
- Cited by
- 512
- References
- 27
- Citations by year
- 2026: 25 · 2025: 41 · 2024: 51 · 2023: 35 · 2022: 47 · 2021: 32 · 2020: 31 · 2019: 25 · 2018: 22 · 2017: 34 · 2016: 29 · 2015: 47 · 2014: 36 · 2013: 39 · 2012: 17
- FWCI
- 29.81
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet Neurology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0508-10123)
- Elan
- National Institute on Aging (K24AG035007, P50AG005134, P30AG062421)
- 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
- Health Sciences › Medicine › Clinical Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- amyloid-related imaging abnormalities, bapineuzumab, Alzheimer's disease, amyloid-beta, ARIA-E, ARIA-H, vasogenic edema, microhemorrhages, APOE ε4, dose-dependent risk, risk factors, FLAIR MRI, adverse events
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Brain, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Retrospective Studies, Risk Factors, Amyloid beta-Peptides, Neuroimaging, Antibodies, Monoclonal, Humanized
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