Amyloid-Related Imaging Abnormalities (ARIA) are the primary safety concern for patients receiving disease modifying therapies (DMTs – e.g., anti-amyloid monoclonal antibodies) for early Alzheimer’s disease. ARIA is characterized by brain swelling (ARIA-E) or bleeding (ARIA-H) and is usually asymptomatic but requires monitoring, especially for APOE ε4 carriers. ARIA can occur in individuals not being treated with DMTs, but at lower rates.

The landscape is rapidly evolving, with ongoing research into predictive biomarkers, individualized risk mitigation, and long-term outcomes.

What is ARIA?

ARIA are MRI-detected brain signal changes believed to be caused by increased vascular permeability triggered by the clearance of amyloid plaques from blood vessel walls. 

ARIA is categorized into two main types: ARIA-E (edema/effusion) and ARIA-H (microhemorrhages or superficial siderosis).

• Prevalence and Severity: ARIA-E is characterized by brain swelling or fluid leakage and occurs in roughly 13-24% of patients. ARIA-E typically resolves within six months of treatment suspension. ARIA-H is characterized by microhemorrhages or superficial iron deposits (siderosis) and affects 17-20% of patients. ARIA-H does not resolve after drug discontinuation.
• Symptoms: Approximately 80% of ARIA cases are asymptomatic and discovered through routine monitoring. When clinical symptoms occur, it they may include headache, confusion, dizziness, and visual changes, although rare severe outcomes like seizures or death have been reported.
• Risk Factors: The most significant risk factor is APOE ε4 carriership, particularly in homozygous carriers (APOE4/4 — carrying two copies of the APOE4 gene) who have a 5.6-fold higher risk compared to non-carriers. Other risks include baseline (e.g., pre-existing) cerebral microhemorrhages, uncontrolled high blood pressure, older age, and concurrent use of antithrombotics. 
• Therapeutic Context: The risk of ARIA varies by drug and treatment  decisions should be made on the basis of individualized risks and benefits. The long-term effects of ARIA are not well understood although recent research on the use of DMTs in patients with recurrent ARIA-E suggests that ARIA does not inevitably lead to accelerated progression and may relate to potential long-term benefits.

Management of ARIA

Currently, preventing ARIA is not fully possible, but risk mitigation involves careful patient selection, medication and blood pressure control, dose titration and monitoring especially during the early months of DMT treatment, and clinically appropriate decision making if ARIA occurs.

• Careful Patient Selection: Due to ARIA risks, up to 90% of some patient populations are currently excluded from receiving these therapies based on clinical trial criteria, such as those with high vascular risk or specific genetic profiles (e.g., APOE4 status).
• Medication Review and Blood Pressure Control: Avoiding or strict monitoring of certain medications like antiplatelet or anticoagulant drugs  and managing known risk factors like blood pressure to reduce the severity of potential ARIA events.
• Dose Titration and Monitoring: Starting anti-amyloid drugs at low doses and slowing increasing while monitoring via baseline and ongoing brain MRIs during the first several months of treatment to detect asymptomatic ARIA before it progresses. Gradual dosing titration has been shown to reduce ARIA-E risk by approximately 40%. The FDA and expert groups like ICARE-AD recommend baseline MRI before starting treatment with regular follow-up scans.
• If ARIA Occurs: ARIA typically occurs early, in the first two to three months (6-8 doses) and is often transient and self-resolving. Management typically involves monitoring with serial MRIs; severe cases may require pausing or permanently discontinuing the therapy.

Key Challenges

• APOE4 Acceleration of Both AD and ARIA Risk: The APOE4 gene increases not only the risk of ARIA but also is the strongest genetic risk factor in the development of AD in older adults. APOE4 increases production of amyloid-beta (Aβ) plaques and impairs Aβ clearance mechanisms, significantly increases the risk and severity of Cerebral Amyloid Angiopathy (CAA) from deposits of these plagues in brain blood vessels and impairment of vascular integrity. APOE4 also enhances tau pathology by activating oxidative stress, disrupting lipid metabolism and triggering inflammatory signaling.
• Risk Prediction and Management: Accurately identifying high-risk individuals before treatment is crucial but remains difficult. Additionally managing diverse and often subtle or asymptomatic symptoms, managing interactions, especially with anticoagulants, standardizing imaging protocols, and understanding the long-term impacts continue to be significant challenges.
• Resource Limitations: Access to MRIs and radiology expertise in ARIA detection for monitoring and specialized neurology, as well as the costs involved in these resources remain a challenge of healthcare system and patient access. The development to AI tools such as the FDA-cleared Icobrain ARIA software for grading ARIA in AD helps bridge the gap between expert and non-expert radiologists.

Future Research Directions

Researchers are investigating novel ways to prevent ARIA, including modified drug delivery mechanisms and drug development beyond amyloid. Innovations in the development of "brain shuttles" or chimeric fusion proteins to clear amyloid without triggering the inflammatory response that causes ARIA is showing promise in reducing ARIA incidence. Additionally, new treatments are in development that expand beyond amyloid, targeting tau, inflammation, vascular issues, and genetic factors. These may not have the same risk of ARIA as current therapies. Clinical trials are also currently testing anti-amyloid antibodies alongside other agents like semaglutide to stabilize blood vessels and FDA- approved anti-inflammatory drugs to prevent the inflammatory response in blood vessels. The shift toward subcutaneous maintenance dosing (e.g., Lecanemab subcutaneous injection) may provide more stable drug levels, potentially lowering the spike in vascular stress associated with IV bolus doses. 

The development of blood-based biomarkers which identify markers like Glial Fibrillary Acid Protein (GFAP), Matrix Metalloproteinases (e.g., MMP3 and MMP10), Phosphorylated Tau (p-tau), and Aβ autoantibodies may allow better prediction of which patients are most likely to develop ARIA before treatment begins. Tracking changes in biomarkers such as Neurofilament Light Chain (NfL) or GPAP can signal the onset or progression of ARIA.

Implications

ARIA is a frequent but usually manageable complication of DMTs in Alzheimer’s disease. Novel approaches to predicting, modelling, preventing, and treating ARIA remain essential to increasing access to DMTs for individuals diagnosed with early AD and addressing real-world data gaps, optimize safety, efficacy, and patient selection particularly in diverse patient populations with potentially different comorbidities than clinical trial populations.

Learn More:

Alzheimer’s Association. Amyloid-Related Imaging Abnormaliites (AERIA in Anti-Amyloid Therapies for Alzheimer’s Disease

Understanding ARIA. ARIA Online Resources and Links.

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