Amyloid-Related Imaging Abnormalities (ARIA)

Introduction

Amyloid Related Imaging Abnormalities (Aria) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

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    AMYLOID["AMYLOID"] -->|"associated with"| MICROGLIA["MICROGLIA"]
    AMYLOID["AMYLOID"] -->|"associated with"| TAU["TAU"]
    AMYLOID["AMYLOID"] -->|"associated with"| BACE1["BACE1"]
    AMYLOID["AMYLOID"] -->|"associated with"| AUTOPHAGY["AUTOPHAGY"]
    AMYLOID["AMYLOID"] -->|"associated with"| APOPTOSIS["APOPTOSIS"]
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    AMYLOID["AMYLOID"] -->|"associated with"| NEURON["NEURON"]
    AMYLOID["AMYLOID"] -->|"associated with"| SOD1["SOD1"]
    AMYLOID["AMYLOID"] -->|"associated with"| NLRP3["NLRP3"]
    AMYLOID["AMYLOID"] -->|"associated with"| SNCA["SNCA"]
    AMYLOID["AMYLOID"] -->|"associated with"| DEPRESSION["DEPRESSION"]
    AMYLOID["AMYLOID"] -->|"inhibits"| ALZHEIMER_S_DISEASE["ALZHEIMER'S DISEASE"]
    AMYLOID["AMYLOID"] -->|"activates"| GENES["GENES"]
    AMYLOID["AMYLOID"] -->|"inhibits"| Alzheimer["Alzheimer"]
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Amyloid-Related Imaging Abnormalities (ARIA) are MRI findings observed in patients receiving anti-amyloid immunotherapy for Alzheimer’s disease. ARIA encompasses two subtypes — ARIA-E (edema/effusion) and ARIA-H (hemorrhage/hemosiderosis) — and represents the most significant safety concern associated with monoclonal antibodies targeting amyloid-beta (Abeta), including lecanemab (Leqembi), donanemab (Kisunla), and aducanumab (Aduhelm) (Sperling et al., 2011; Sperling et al., 2019). ^{1Lecanemab in Early Alzheimer's Disease (2023)2023 · DOI 10.1056/NEJMoa2212948Open reference 2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}

Understanding ARIA is critical as anti-amyloid therapeutics enter routine clinical practice. While most cases are asymptomatic and resolve with appropriate management, severe ARIA can cause serious neurological complications and, rarely, death. The emergence of ARIA as a clinical entity has reshaped how anti-amyloid therapies are administered and monitored. ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference 3Donanemab in Early Symptomatic Alzheimer's Disease (2023)2023 · DOI 10.1001/jama.2023.13239Open reference}

Types of ARIA

ARIA-E (Edema/Effusion)

ARIA-E refers to amyloid-related imaging abnormalities with edema or sulcal effusion, appearing as hyperintense signal on T2-weighted FLAIR MRI sequences (Barakos et al., 2022): ^{3Donanemab in Early Symptomatic Alzheimer's Disease (2023)2023 · DOI 10.1001/jama.2023.13239Open reference 4Lecanemab: Appropriate Use Recommendations (2023)2023 · DOI 10.14283/jpad.2023.30Open reference}

• Imaging appearance: Patchy or confluent hyperintensity in brain parenchyma (vasogenic edema) and/or sulcal effusion (fluid in the sulci and subarachnoid space)

• Most common locations: Posterior brain regions (occipital and parietal lobes), though any cortical region may be affected

• Temporal pattern: Usually occurs within the first 3-6 months of treatment, most commonly before the 5th infusion

• Resolution: Typically resolves within 3-4 months with treatment suspension; can recur upon re-initiation

• Incidence: 10-35% depending on drug, dose, and patient population ^{4Lecanemab: Appropriate Use Recommendations (2023)2023 · DOI 10.14283/jpad.2023.30Open reference}

ARIA-H (Hemorrhage/Hemosiderosis)

ARIA-H encompasses hemorrhagic or hemosiderotic changes detected on susceptibility-weighted imaging (SWI) or T2*-weighted gradient echo MRI: ^{5The effect of modified donanemab titration on ARIA (2025)2025 · DOI 10.1016/j.tjpad.2025.100266Open reference}

• Cerebral microbleeds (CMBs): Small, round, hypointense lesions representing focal hemosiderin deposits

• Cortical superficial siderosis (cSS): Linear hypointensities along the cortical surface

• Larger intracerebral hemorrhages: Rare but can be severe or fatal

• Incidence: 5-31% in clinical trials; ARIA-H microbleeds are more common than cSS ^{6Amyloid-Related Imaging Abnormalities with Emerging AD Therapeutics (2022)2022 · DOI 10.3174/ajnr.A7586Open reference}

ARIA-E and ARIA-H Co-occurrence

The two subtypes frequently co-occur — approximately 40-50% of patients with ARIA-E also develop ARIA-H. ARIA-H may persist after ARIA-E resolves, as hemosiderin deposits are permanent. ^{7Alzheimer's Disease Anti-Amyloid Immunotherapies: Imaging Recommendations (2025)2025 · DOI 10.3174/ajnr.A8469Open reference 2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}0

Pathophysiology

Vascular Amyloid Clearance Mechanism

The leading hypothesis links ARIA to the interaction between anti-amyloid antibodies and cerebral amyloid angiopathy (CAA) (Greenberg et al., 2017; Barakos et al., 2022): ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}1 ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}2

1. Baseline vascular amyloid: In AD patients, Aβ deposits in the walls of leptomeningeal and cortical arterioles and capillaries (CAA), weakening vessel walls

2. Antibody engagement: Anti-Aβ monoclonal antibodies bind to vascular amyloid deposits, triggering an inflammatory response

3. Vascular permeability increase: Antibody-mediated inflammation and complement activation damage the already-compromised vessel walls, increasing permeability

4. ARIA-E formation: Proteinaceous fluid leaks through damaged vessel walls into the brain parenchyma (vasogenic edema) and subarachnoid space (sulcal effusion)

5. ARIA-H formation: Blood products leak through the damaged walls, producing microbleeds or, in severe cases, larger hemorrhages ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}3

Immunological Mechanisms

Additional immunological processes contribute to ARIA: ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}4

• Fc-mediated effector functions: Antibody Fc regions engage [Microglia:

Lecanemab (biweekly infusions): ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}5

• Baseline MRI before treatment initiation

• MRI before the 3rd, 5th, 7th, and 14th infusions (approximately weeks 4, 8, 12, and 26)

• Additional imaging if symptoms develop

Donanemab (monthly infusions): ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}6

• Baseline MRI

• MRI before the 3rd, 4th, and 5th infusions (approximately months 2, 3, and 4)

• Additional imaging as clinically indicated

Treatment Algorithm for ARIA

Asymptomatic ARIA-E: ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}7

• Consider temporary treatment suspension

• Repeat MRI in 2-4 months

• Resume treatment once ARIA-E has radiographically resolved

Symptomatic ARIA-E: ^{2Amyloid-related imaging abnormalities (ARIA): radiological, biological and clinical characteristics (2023)2023 · DOI 10.1093/brain/awad188Open reference}8

• Suspend treatment

• Consider corticosteroids (high-dose methylprednisolone or oral prednisone) for significant edema

• Monitor with serial MRI every 4-8 weeks until resolution

• Resume treatment only after complete radiographic resolution and symptom resolution

ARIA-H (microbleeds):

• ≤4 new microbleeds: May continue with enhanced monitoring

• 5-9 new microbleeds: Consider suspension; reassess with follow-up imaging

• ≥10 new microbleeds or any macrohemorrhage: Permanently discontinue

Permanent discontinuation indications:

• Recurrent symptomatic ARIA-E

• Severe ARIA-E not resolving within expected timeframe

• Macrohemorrhage >1 cm

• ≥10 new microbleeds

ARIA by Drug

Lecanemab (Leqembi)

Lecanemab is a humanized monoclonal antibody targeting soluble Aβ protofibrils, approved by the FDA in January 2023 (accelerated) and July 2023 (traditional approval), and by the EMA in late 2024:

• CLARITY-AD trial (n=1,795): ARIA-E incidence 12.6%, ARIA-H microbleeds 17.3%, cSS 14.0%

• Symptomatic ARIA-E: 2.8%; most cases resolved within 4 months

• Three deaths potentially related to ARIA (including in patients on anticoagulants)

• APOE ε4

4. Cummings J et al., Lecanemab: Appropriate Use Recommendations (2023)

5. Wang H et al., The effect of modified donanemab titration on amyloid-related imaging abnormalities with edema/effusions and amyloid reduction: 18-month results from TRAILBLAZER-ALZ 6 (2025)

6. Cogswell PM et al., Amyloid-Related Imaging Abnormalities with Emerging Alzheimer’s Disease Therapeutics: Detection and Reporting Recommendations for Clinical Practice (2022)

7. Cogswell PM et al., Alzheimer’s Disease Anti-Amyloid Immunotherapies: Imaging Recommendations and Practice Considerations for Monitoring of Amyloid-Related Imaging Abnormalities (2025)

8. Zimmer JA et al., Amyloid-Related Imaging Abnormalities With Donanemab in Early Symptomatic Alzheimer’s Disease: Secondary Analysis of the TRAILBLAZER-ALZ and ALZ 2 Randomized Clinical Trials (2025)

Brain Atlas Resources

• Allen Human Brain Atlas: Amyloid-Related Imaging Abnormalities expression search

• Allen Mouse Brain Atlas: Amyloid-Related Imaging Abnormalities search

• Allen Cell Type Atlas: Transcriptomic cell type reference

• BrainSpan Developmental Transcriptome: Amyloid-Related Imaging Abnormalities developmental expression

See Also

• Neurodegenerative Diseases

• Disease Mechanisms

• All Pages

External Links

• PubMed

Background

The study of Amyloid Related Imaging Abnormalities (Aria) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.