Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup
Open accessAbstract
Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-β burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent "vasogenic edema" and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research.
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Aducanumab, as with other mAbs, can induce radiographic features known as AD-related imaging abnormalities with edema (ARIA-E) or hemorrhage (ARIA-H).
“In addition, Aducanumab, as with other mAbs, can induce radiographic features known as AD-related imaging abnormalities with edema (ARIA-E) or hemorrhage (ARIA-H) [66].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [66]
The sections on ARIA-E alterations and the association between ARIA components describe edema-like MRI abnormalities and microhemorrhages in trials of bapineuzumab, an anti-amyloid monoclonal antibody. The paper supports the general association with this class of therapy, but our copy does not identify aducanumab or establish that it specifically induces ARIA-E or ARIA-H. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE ε4 carrier status is associated with an increased rate of microbleeds and vasogenic edema.
“Although clinical trials of the Aβ-directed mAb Bapinezumab showed no clear cognitive benefits in patients with mild to moderate AD [42], the results also indicated that APOE ε4 carrier status may limit the response to anti-Aβ passive immunization [43,44], as well as being associated with an increased rate of microbleeds and vasogenic edema [45].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [45]
The Risk factors for ARIA-E section reports that APOE ε4 was a significant risk factor for vasogenic edema in the Phase II bapineuzumab trial. The Association between components of ARIA section says data on incident microhemorrhages are limited; it does not establish a higher microbleed rate in ε4 carriers. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe main adverse effects associated with administration of certain anti-Aβ mAbs during clinical trials were amyloid related imaging abnormalities (ARIA) identified on MRI scans.
“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 [13]
The Introduction reports MRI abnormalities first observed in trials of an anti-Aβ monoclonal antibody, and “The phenomenon formerly known as ‘VE’: ARIA-E alterations” describes ARIA-like MRI findings after bapineuzumab dosing. The “Clinical course associated with ARIA-E” section also reports cases detected on trial MRI scans. These passages support ARIA as a treatment-associated safety concern, but do not establish that it was the main adverse effect relative to others. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn about 20% of ARIA cases, they are associated with clinical symptoms and signs.
“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 [13]
The Clinical course associated with ARIA-E section (page unavailable) reports that 2 of 12 Phase II bapineuzumab ARIA-E cases were symptomatic enough to prompt an off-protocol MRI—approximately 17%. It also reports transient symptoms in four more cases, so the paper does not establish that about 20% of ARIA-E and ARIA-H cases overall are associated with clinical symptoms and signs. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA consensus group from the US Alzheimer's Association has published standards for assessing microbleeds in the context of Alzheimer's disease or β-amyloid immunotherapies.
“A consensus group from the US Alzheimer's Association has published standards for assessing microbleeds in this specific clinical context,61”
From Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration (2013) · cites this paper as [61]
ARIA included vasogenic edema (ARIA-E) and cerebral microhemorrhages (ARIA-H).
“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 [13]
pE3Aβ is present at low concentrations but is often associated with dense core plaques.
“The pE3Aβ is present at low concentrations, but often associated with dense core plaques 56,78 .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [56]
Donanemab has a high incidence of ARIA (27%), which was not evident in preclinical studies.
“Interestingly, donanemab has a high incidence of ARIA (27%), although this was not evident in preclinical studies 56 .”
From The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics (2022) · cites this paper as [56]
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Research works printed but not linked: 3
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- [38]Goos JD Stroke In Press
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“Although the mechanism leading to ARIA remains not fully understood, studies suggest that Aβ clearance causes damage to vessel walls which increases the cerebrovascular permeability and the risk of hemorrhage.(52,53) ARIA has been associated with anti-Aβ antibodies therapies and was reported in the phase 1b trial of a…”
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“Also, if disease-modifying drugs are introduced into the clinic,MRIGradient Echo sequencemay allow to detect cerebral amyloid angiopathywhich is associated with a higher risk for AmyloidRelated Imaging Abnormalities (Sperling et al., 2011), as seen in most passive immunization trials.”
BackgroundAmyloid-Related Imaging Abnormalities: An Update
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“In addition, Aducanumab, as with other mAbs, can induce radiographic features known as AD-related imaging abnormalities with edema (ARIA-E) or hemorrhage (ARIA-H) [66].”
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Self-citationImaging of cerebrovascular pathology in animal models of Alzheimer's disease
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“ARIA can underlie vasogenic edema (ARIA-E), or microhemorrhages and cortical superficial siderosis (ARIA-H) [88] and is usually asymptomatic, although in some cases headache, lethargy, confusion, or behavioral changes can occur [87].”
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Self-citationAβ immunotherapy for Alzheimer’s disease: effects on apoE and cerebral vasculopathy
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Transferrin receptor-targeted anti-amyloid antibody enhances brain delivery and mitigates ARIA.
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Aducanumab anti-amyloid immunotherapy induces sustained microglial and immune alterations
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“and cerebral microhemorrhages (ARIA-H) that in about 20% of cases are associated with clinical symptoms and signs [13, 14].”
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“Various risk factors of ARIA have been reported in clinical trials of anti-A β immunotherapy [6,14,25,26].”
BackgroundMethodInfluentialAntibody Engineering for Optimized Immunotherapy in Alzheimer's Disease
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“Although monoclonal antibodies such as Aducanumab and Lecanemab reduce plaque burden and modestly slow cognitive decline, they are associated with a high incidence of amyloid-related imaging abnormalities (ARIA), including vaso-genic edema (ARIA-E) and microhemorrhages (ARIA-H) [ 7, 9–11 ].”
- Authors
- Sperling, R. A., Jack, C. R., Black, S. E., Frosch, M. P., Greenberg, S. M., Hyman, B. T., Scheltens, P., Carrillo, M. C., Thies, W., Bednar, M. M., Black, R. S., Brashear, H. R., Grundman, M., Siemers, E. R., Feldman, H. H., & Schindler, R. J.
- Affiliations
- Brigham and Women's Hospital (US)
- Mayo Clinic (US)
- Sunnybrook Health Science Centre (CA)
- Harvard University (US)
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Alzheimer's Association (US)
- Pfizer (United States) (US)
- Janssen Alzheimer Immunotherapy Research & Development (United States) (US)
- Eli Lilly (United States) (US)
- Yale University (US)
- Corresponding author
- Sperling, Reisa A.
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 7
- Issue
- 4
- Pages
- 367-385
- ISSN
- 1552-5260 (ISSN-L)
- PMC
- PMC3693547
- OpenAlex
- W2108216694
- Cited by
- 857
- References
- 104
- Citations by year
- 2026: 99 · 2025: 121 · 2024: 90 · 2023: 89 · 2022: 76 · 2021: 50 · 2020: 42 · 2019: 27 · 2018: 30 · 2017: 26 · 2016: 44 · 2015: 28 · 2014: 43 · 2013: 47 · 2012: 37
- FWCI
- 28.80
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (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)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Institute on Aging (K24AG035007, P50AG005134)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Keywords
- amyloid-related imaging abnormalities, aria
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Brain Edema, Cerebral Hemorrhage, Clinical Trials as Topic, Disease Models, Animal, Humans, Magnetic Resonance Imaging, Societies, Medical
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