CoChat
Sign Up
Cited by 412Alzheimer's disease research and treatmentsIntracerebral and Subarachnoid Hemorrhage ResearchDementia and Cognitive Impairment Research

Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics

Open access
Hampel, Harald, Elhage, Aya, Cho, Min, Apostolova, Liana G, Nicoll, James A R, Atri, Alireza·2023·Brain
DOI 10.1093/brain/awad188PMC PMC10629981
Open this paper in CoChat — free accountOpen PDF

Abstract

Excess accumulation and aggregation of toxic soluble and insoluble amyloid-β species in the brain are a major hallmark of Alzheimer’s disease. Randomized clinical trials show reduced brain amyloid-β deposits using monoclonal antibodies that target amyloid-β and have identified MRI signal abnormalities called amyloid-related imaging abnormalities (ARIA) as possible spontaneous or treatment-related adverse events. This review provides a comprehensive state-of-the-art conceptual review of radiological features, clinical detection and classification challenges, pathophysiology, underlying biological mechanism(s) and risk factors/predictors associated with ARIA. We summarize the existing literature and current lines of evidence with ARIA-oedema/effusion (ARIA-E) and ARIA-haemosiderosis/microhaemorrhages (ARIA-H) seen across anti-amyloid clinical trials and therapeutic development. Both forms of ARIA may occur, often early, during anti-amyloid-β monoclonal antibody treatment. Across randomized controlled trials, most ARIA cases were asymptomatic. Symptomatic ARIA-E cases often occurred at higher doses and resolved within 3–4 months or upon treatment cessation. Apolipoprotein E haplotype and treatment dosage are major risk factors for ARIA-E and ARIA-H. Presence of any microhaemorrhage on baseline MRI increases the risk of ARIA. ARIA shares many clinical, biological and pathophysiological features with Alzheimer’s disease and cerebral amyloid angiopathy. There is a great need to conceptually link the evident synergistic interplay associated with such underlying conditions to allow clinicians and researchers to further understand, deliberate and investigate on the combined effects of these multiple pathophysiological processes. Moreover, this review article aims to better assist clinicians in detection (either observed via symptoms or visually on MRI), management based on appropriate use recommendations, and general preparedness and awareness when ARIA are observed as well as researchers in the fundamental understanding of the various antibodies in development and their associated risks of ARIA. To facilitate ARIA detection in clinical trials and clinical practice, we recommend the implementation of standardized MRI protocols and rigorous reporting standards. With the availability of approved amyloid-β therapies in the clinic, standardized and rigorous clinical and radiological monitoring and management protocols are required to effectively detect, monitor, and manage ARIA in real-world clinical settings.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/brain/awad188

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In patients with early-stage AD, coexistence of pathology from other etiologies, such as VD, can increase the risk of amyloid-related imaging abnormalities.

    “For example, although patients with early-stage AD may be candidates for anti-amyloid therapies15–17, the coexistence of pathology from other etiologies, such as VD, can increase the risk of amyloid-related imaging abnormalities18.”

    From AI-based differential diagnosis of dementia etiologies on multimodal data (2024) · cites this paper as [18]

    The Risk factors and predictors of ARIA section (page unavailable) says severe cerebral amyloid angiopathy or baseline microhaemorrhages increase ARIA risk and lists pre-existing cerebrovascular disease among conditions that may predispose to ARIA. It does not specifically establish that coexisting vascular dementia (VD) increases ARIA risk in patients with early-stage Alzheimer’s disease. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 64

  1. [2]Hampel H, Hardy J, Blennow K, et al The amyloid-β pathway in Alzheimer's disease. Mol Psychiatry. 2021; 26: 5481– 5503. 34456336 PMC8758495
  2. [3]Dubois B, Feldman HH, Jacova C, et al Advancing research diagnostic criteria for Alzheimer's disease: The IWG-2 criteria. Lancet Neurol. 2014; 13: 614– 629. 24849862
  3. [4]Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: New insights from new therapeutics. Nat Rev Drug Discov. 2022; 21: 306– 318. 35177833
  4. [5]Hampel H, Cummings J, Blennow K, Gao P, Jack C, Vergallo A. Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat Rev Neurol. 2021; 17: 580– 589. 34239130
  5. [6]van Dyck CH, Swanson CJ, Aisen P, et al Lecanemab in early Alzheimer's disease. N Engl J Med. 2022; 388: 9– 21. 36449413
  6. [7]Filippi M, Cecchetti G, Spinelli EG, Vezzulli P, Falini A, Agosta F. Amyloid-related imaging abnormalities and beta-amyloid-targeting antibodies: A systematic review. JAMA Neurol. 2022; 79: 291– 304. 35099507
  7. [8]Sperling RA, Jack CR, Black SE, et al Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations from the Alzheimer's association research roundtable workgroup. Alzheimers Dement. 2011; 7: 367– 385. 21784348 PMC3693547
  8. [9]Barakos J, Sperling R, Salloway S, et al MR Imaging features of amyloid-related imaging abnormalities. AJNR Am J Neuroradiol. 2013; 34: 1958– 1965. 23578674 PMC7965435
  9. [10]Barakos J, Purcell D, Suhy J, et al Detection and management of amyloid-related imaging abnormalities in patients with Alzheimer's disease treated with anti-amyloid Beta therapy. J Prev Alzheimers Dis. 2022; 9: 211– 220. 35542992
  10. [12]Cogswell PM, Barakos JA, Barkhof F, et al Amyloid-Related imaging abnormalities with emerging Alzheimer disease therapeutics: Detection and reporting recommendations for clinical practice. AJNR Am J Neuroradiol. 2022; 43: E19– E35. 35953274 PMC9451628
  11. [13]Liu E, Wang D, Sperling R, et al Biomarker pattern of ARIA-E participants in phase 3 randomized clinical trials with bapineuzumab. Neurology. 2018; 90: e877– e886. 29429971
  12. [14]Arrighi HM, Barakos J, Barkhof F, et al Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer's disease treated with bapineuzumab: A historical, prospective secondary analysis. J Neurol Neurosurg Psychiatry. 2016; 87: 106– 112. 25669746 PMC4717448
  13. [15]Cummings J, Rabinovici GD, Atri A, et al Aducanumab: Appropriate use recommendations update. J Prev Alzheimer's Dis. 2022; 9: 221– 230. 35542993 PMC9169517
  14. [16]Cummings JL, Cohen S, van Dyck CH, et al ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018; 90: e1889– e1897. 29695589 PMC5962917
  15. [17]Cummings J, Aisen P, Apostolova L, Atri A, Salloway S, Weiner M. Aducanumab: Appropriate use recommendations. J Prev Alzheimers Dis. 2021; 8: 398– 410. 34585212 PMC8835345
  16. [21]Ferrer I, Boada Rovira M, Sánchez Guerra ML, Rey MJ, Costa-Jussá F. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004; 14: 11– 20. 14997933 PMC8095815
  17. [22]Carlson C, Siemers E, Hake A, et al Amyloid-related imaging abnormalities from trials of solanezumab for Alzheimer's disease. Alzheimers Dement (Amst). 2016; 2: 75– 85. 27239538 PMC4879647
  18. [23]Blitstein MK, Tung GA. MRI Of cerebral microhemorrhages. AJR Am J Roentgenol. 2007; 189: 720– 725. 17715122
  19. [24]Viswanathan A, Chabriat H. Cerebral microhemorrhage. Stroke. 2006; 37: 550– 555. 16397165
  20. [26]Parodi-Rullán R, Sone JY, Fossati S. Endothelial mitochondrial dysfunction in cerebral amyloid angiopathy and Alzheimer's disease. J Alzheimers Dis. 2019; 72: 1019– 1039. 31306129 PMC6917858
  21. [27]Wermer MJH, Greenberg SM. The growing clinical spectrum of cerebral amyloid angiopathy. Curr Opin Neurol. 2018; 31: 28– 35. 29120920
  22. [28]Biffi A, Greenberg SM. Cerebral amyloid angiopathy: A systematic review. J Clin Neurol. 2011; 7: 1– 9. 21519520 PMC3079153
  23. [29]Jellinger KA. Alzheimer Disease and cerebrovascular pathology: An update. J Neural Transm (Vienna). 2002; 109(5–6): 813– 836. 12111471
  24. [30]Miners JS, Baig S, Palmer J, Palmer LE, Kehoe PG, Love S. Abeta-degrading enzymes in Alzheimer's disease. Brain Pathol. 2008; 18: 240– 252. 18363935 PMC8095507
  25. [31]Boyle PA, Yu L, Nag S, et al Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology. 2015; 85: 1930– 1936. 26537052 PMC4664125
  26. [32]Hampel H, Gao P, Cummings J, et al The foundation and architecture of precision medicine in neurology and psychiatry. Trends Neurosci. 2023; 46: 176– 198. 36642626 PMC10720395
  27. [33]Antolini L, DiFrancesco JC, Zedde M, et al Spontaneous ARIA-like events in cerebral amyloid angiopathy-related inflammation: A multicenter prospective longitudinal cohort study. Neurology. 2021; 97: e1809– e1822. 34531298 PMC8610623
  28. [34]Banerjee G, Carare R, Cordonnier C, et al The increasing impact of cerebral amyloid angiopathy: Essential new insights for clinical practice. J Neurol Neurosurg Psychiatry. 2017; 88: 982– 994. 28844070 PMC5740546
  29. [37]Leurent C, Goodman JA, Zhang Y, et al Immunotherapy with ponezumab for probable cerebral amyloid angiopathy. Ann Clin Transl Neurol. 2019; 6: 795– 806. 31020004 PMC6469253
  30. [38]Penninkilampi R, Brothers HM, Eslick GD. Safety and efficacy of anti-amyloid-β immunotherapy in Alzheimer's disease: A systematic review and meta-analysis. J Neuroimmune Pharmacol. 2017; 12: 194– 203. 28025724
  31. [39]Orgogozo JM, Gilman S, Dartigues JF, et al Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003; 61: 46– 54. 12847155
  32. [41]Scherlek AA, Kozberg MG, Nicoll JAR, et al Histopathological correlates of haemorrhagic lesions on ex vivo magnetic resonance imaging in immunized Alzheimer's disease cases. Brain Commun. 2022; 4: fcac021. 35224489 PMC8870423
  33. [42]Nicoll JAR, Buckland GR, Harrison CH, et al Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer's disease. Brain. 2019; 142: 2113– 2126. 31157360 PMC6598630
  34. [43]Carare RO, Aldea R, Agarwal N, et al Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of vascular professional interest area (PIA): Cerebrovascular disease and the failure of elimination of amyloid-β from the brain and retina with age and Alzheimer's disease-opportunities for therapy. Alzheimers Dement (Amst). 2020; 12: e12053. 32775596 PMC7396859
  35. [44]Boche D, Zotova E, Weller RO, et al Consequence of abeta immunization on the vasculature of human Alzheimer's disease brain. Brain. 2008; 131: 3299– 3310. 18953056
  36. [47]Zago W, Schroeter S, Guido T, et al Vascular alterations in PDAPP mice after anti-aβ immunotherapy: Implications for amyloid-related imaging abnormalities. Alzheimers Dement. 2013; 9: S105– S115. 23583235
  37. [48]Piazza F, Greenberg SM, Savoiardo M, et al Anti-amyloid beta autoantibodies in cerebral amyloid angiopathy-related inflammation: Implications for amyloid-modifying therapies. Ann Neurol. 2013; 73: 449– 458. 23625526
  38. [49]van Dyck CH. Anti-amyloid-beta monoclonal antibodies for Alzheimer's dsease: Pitfalls and promise. Biol Psychiatry. 2018; 83: 311– 319. 28967385 PMC5767539
  39. [50]Chantran Y, Capron J, Alamowitch S, Aucouturier P. Anti-abeta antibodies and cerebral amyloid angiopathy complications. Front Immunol. 2019; 10: 1534. 31333665 PMC6620823
  40. [53]Ketter N, Brashear HR, Bogert J, et al Central review of amyloid-related imaging abnormalities in two phase III clinical trials of bapineuzumab in mild-to-moderate Alzheimer's disease patients. J Alzheimers Dis. 2017; 57: 557– 573. 28269765
  41. [54]Yaari R, Holdridge KC, Choi J, et al Amyloid-Related imaging abnormalities and other MRI findings in a cognitively unimpaired population with and without cerebral amyloid. J Prev Alzheimers Dis. 2022; 9: 617– 624. 36281665 PMC10966506
  42. [55]VandeVrede L, Gibbs DM, Koestler M, et al Symptomatic amyloid-related imaging abnormalities in an APOE epsilon4/epsilon4 patient treated with aducanumab. Alzheimers Dement (Amst). 2020; 12: e12101. 33072846 PMC7545921
  43. [56]Ostrowitzki S, Lasser RA, Dorflinger E, et al A phase III randomized trial of gantenerumab in prodromal Alzheimer's disease. Alzheimers Res Ther. 2017; 9: 95. 29221491 PMC5723032
  44. [57]Budd Haeberlein S, O'Gorman J, Chiao P, et al Clinical development of aducanumab, an anti-abeta human monoclonal antibody being investigated for the treatment of early Alzheimer's disease. J Prev Alzheimers Dis. 2017; 4: 255– 263. 29181491
  45. [60]Withington CG, Turner RS. Amyloid-Related imaging abnormalities with anti-amyloid antibodies for the treatment of dementia due to Alzheimer's disease. Front Neurol. 2022; 13: 862369. 35401412 PMC8985815
  46. [61]Brenowitz WD, Nelson PT, Besser LM, Heller KB, Kukull WA. Cerebral amyloid angiopathy and its co-occurrence with Alzheimer's disease and other cerebrovascular neuropathologic changes. Neurobiol Aging. 2015; 36: 2702– 2708. 26239176 PMC4562901
  47. [62]Herzig MC, Van Nostrand WE, Jucker M. Mechanism of cerebral beta-amyloid angiopathy: Murine and cellular models. Brain Pathol. 2006; 16: 40– 54. 16612981 PMC8095938
  48. [63]Ringman JM, Sachs MC, Zhou Y, Monsell SE, Saver JL, Vinters HV. Clinical predictors of severe cerebral amyloid angiopathy and influence of APOE genotype in persons with pathologically verified Alzheimer disease. JAMA Neurol. 2014; 71: 878– 883. 24797962 PMC4101018
  49. [64]Nicoll JA, Burnett C, Love S, et al High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1997; 41: 716– 721. 9189032
  50. [65]Biffi A, Sonni A, Anderson CD, et al Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann Neurol. 2010; 68: 934– 943. 21061402 PMC3058266
  51. [66]Roh D, Schmidt JM, Roth W, et al Risk factors associated with cerebral amyloid angiopathy lobar hemorrhage: A single center cohort analysis (P6.056). Neurology. 2016; 86: P6.056.
  52. [67]Salloway S, Chalkias S, Barkhof F, et al Amyloid-related imaging abnormalities in 2 phase 3 studies evaluating aducanumab in patients with early Alzheimer disease. JAMA Neurol. 2021; 79: 13– 21. PMC8609465 34807243
  53. [68]DiFrancesco JC, Longoni M, Piazza F. Anti-abeta autoantibodies in amyloid related imaging abnormalities (ARIA): Candidate biomarker for immunotherapy in Alzheimer's disease and cerebral amyloid angiopathy. Front Neurol. 2015; 6: 207. 26441825 PMC4585101
  54. [69]Hampel H, Shaw LM, Aisen P, et al State-of-the-art of lumbar puncture and its place in the journey of patients with Alzheimer's disease. Alzheimers Dement. 2022; 18: 159– 177. 34043269 PMC8626532
  55. [70]Piazza F, Winblad B. Amyloid-related imaging abnormalities (ARIA) in immunotherapy trials for Alzheimer's disease: Need for prognostic biomarkers? J Alzheimers Dis. 2016; 52: 417– 420. 27031492
  56. [71]Raman MR, Wiste HJ, Senjem ML, Ward CP, Jack CR, Kantarci K. Spontaneous amyloid-related imaging abnormalities in a cognitively normal adult. Neurology. 2014; 83: 1771– 1772. 25367059 PMC4239833
  57. [72]Carlson C, Estergard W, Oh J, et al Prevalence of asymptomatic vasogenic edema in pretreatment Alzheimer's disease study cohorts from phase 3 trials of semagacestat and solanezumab. Alzheimers Dement. 2011; 7: 396– 401. 21784350
  58. [73]Vernooij MW, van der Lugt A, Ikram MA, et al Prevalence and risk factors of cerebral microbleeds: The Rotterdam Scan Study. Neurology. 2008; 70: 1208– 1214. 18378884
  59. [74]Atri A, Locascio JJ, Lin JM, et al Prevalence and effects of lobar microhemorrhages in early-stage dementia. Neurodegener Dis. 2005; 2: 305– 312. 16909013
  60. [75]Cordonnier C, van der Flier WM. Brain microbleeds and Alzheimer's disease: Innocent observation or key player? Brain. 2011; 134: 335– 344. 21257651
  61. [77]Gleason A, Ayton S, Bush AI. Unblinded by the light: Amyloid-related imaging abnormalities in Alzheimer's clinical trials. Eur J Neurol. 2021; 28: e1. 32808453
  62. [78]Cordonnier C, Potter GM, Jackson CA, et al Improving interrater agreement about brain microbleeds: Development of the brain observer MicroBleed scale (BOMBS). Stroke. 2009; 40: 94– 99. 19008468
  63. [79]Barkhof F, Daams M, Scheltens P, et al An MRI rating scale for amyloid-related imaging abnormalities with edema or effusion. AJNR Am J Neuroradiol. 2013; 34: 1550– 1555. 23436056 PMC8051438
  64. [80]Mokli Y, Pfaff J, Dos Santos DP, Herweh C, Nagel S. Computer-aided imaging analysis in acute ischemic stroke—Background and clinical applications. Neurol Res Pract. 2019; 1: 23. 33324889 PMC7650084

Cited by

Sorted by citations

Authors
Hampel, H., Elhage, A., Cho, M., Apostolova, L. G., Nicoll, J. A. R., & Atri, A.
Affiliations
  • Eisai (United States) (US)
  • Indiana University Hospital (US)
  • University Hospital Southampton NHS Foundation Trust (GB)
  • Brigham and Women's Hospital (US)
Corresponding author
Hampel, Harald
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2023-06-06
Volume
146
Issue
11
Pages
4414-4424
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awad188
PMC
PMC10629981
OpenAlex
W4379600618
Cited by
412
References
12
Citations by year
2026: 163 · 2025: 152 · 2024: 85 · 2023: 12
FWCI
14.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc)
  • ePrints Soton (University of Southampton) (submittedVersion)
Funders
  • Eisai
  • National Institute on Aging (P30AG072980)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid-related imaging abnormalities, aria, amyloid-beta, Alzheimer's disease, anti-amyloid monoclonal antibodies, ARIA-E, ARIA-H, cerebral edema, cerebral amyloid angiopathy, apolipoprotein E, treatment-related adverse events, amyloid-beta aggregation
MeSH terms
Alzheimer Disease, Amyloid, Brain, Humans, Amyloid beta-Peptides, Amyloidogenic Proteins, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review