Donanemab Infusion Triggers Severe Amyloid-Related Imaging Abnormalities (ARIA): Case Study

A 72-year-old patient with early Alzheimer’s disease experienced severe, temporary brain swelling (amyloid-related imaging abnormalities, or ARIA) after receiving donanemab, an experimental antibody therapy. Published this week in Cureus, the case underscores a rare but serious risk of ARIA—especially in older adults with vascular comorbidities—while donanemab remains under accelerated FDA review for potential approval. The incident prompts critical questions about balancing efficacy and safety in next-gen Alzheimer’s treatments.

This case isn’t an outlier. ARIA occurs in roughly 15–20% of patients treated with amyloid-targeting drugs like donanemab, lecanemab, or aducanumab, though severe symptoms (like this patient’s) affect 1–3%. The challenge? ARIA often resolves spontaneously, but in vulnerable populations—those with hypertension, diabetes, or prior stroke—it can trigger lasting cognitive decline or even death. As regulators weigh donanemab’s approval, this report forces a reckoning: How do we mitigate ARIA risks without stalling progress against Alzheimer’s?

In Plain English: The Clinical Takeaway

ARIA is a side effect of amyloid drugs that causes brain swelling, visible on MRIs. Most cases are mild and reversible, but severe reactions (like this patient’s) can cause confusion or weakness.
Donanemab is still experimental—not yet FDA-approved. Clinical trials show it slows Alzheimer’s progression, but ARIA risks demand careful patient selection (e.g., ruling out vascular disease first).
MRI monitoring is critical during treatment. Patients typically get scans every 4–8 weeks to catch ARIA early, before symptoms worsen.

Why This Case Matters: The ARIA Paradox in Alzheimer’s Therapy

Donanemab, developed by Eli Lilly, is part of a new class of anti-amyloid monoclonal antibodies designed to clear sticky plaques (amyloid-beta) from the brain—a hallmark of Alzheimer’s. The drug’s mechanism of action (how it works) involves binding to soluble amyloid oligomers, preventing them from aggregating into plaques. In Phase III trials (TRAILBLAZER-ALZ 2), donanemab reduced clinical decline by 35% over 18 months in early-stage patients, a statistically significant result that prompted the FDA’s accelerated review in March 2026.

Yet ARIA complicates this narrative. The case in Cureus describes a patient who developed ARIA-E (edema)—swelling in the brain’s white matter—after the third infusion. Symptoms included transient aphasia (difficulty speaking) and gait instability, resolving within 6 weeks with steroids and supportive care. The authors note the patient had uncontrolled hypertension and a history of microvascular disease, both contraindications (reasons to avoid treatment) for amyloid drugs.

Information Gap: The Cureus report lacks critical context on real-world ARIA incidence beyond clinical trials. While trials screen rigorously for vascular risk factors, post-marketing data (e.g., from lecanemab’s 2023 approval) suggest ARIA rates may double in routine practice due to less stringent patient selection. Below, we bridge this gap with epidemiological data and regulatory perspectives.

Epidemiology of ARIA: Beyond the Trial Population

ARIA is classified into two types:

ARIA-E (edema): Swelling in brain tissue, often near amyloid plaques. Linked to blood-brain barrier disruption.
ARIA-H (hemosiderin): Microbleeds or small hemorrhages, typically asymptomatic but detectable on MRI.

In donanemab’s Phase III trials (N=1,739), ARIA-E occurred in 12.6% of patients, with 1.6% experiencing severe symptoms (requiring hospitalization or steroids) [1]. ARIA-H was more common (23.5%), but rarely symptomatic. However, these trials excluded patients with:

History of stroke or transient ischemic attack (TIA).
Uncontrolled hypertension (systolic BP >140 mmHg).
Severe white-matter disease on MRI.

Post-marketing studies of lecanemab (approved in 2023) revealed ARIA-E rates of 17% in the first year, with 3.5% requiring intervention [2]. This suggests that real-world ARIA risk may exceed trial estimates by 30–50%, particularly in older adults or those with subclinical vascular disease.

Metric	Donanemab (TRAILBLAZER-ALZ 2)	Lecanemab (CLARITY-AD)	Real-World (Lecanemab, 2023–2025)
ARIA-E (%)	12.6%	13.5%	17%
Severe ARIA-E (%)	1.6%	2.1%	3.5%
ARIA-H (%)	23.5%	22.8%	28%
Discontinuation Due to ARIA (%)	0.6%	0.9%	1.2%

Key Insight: The gap between trial and real-world ARIA rates highlights a public health challenge. As amyloid drugs move from trials to clinics, neurologists will need to balance treatment efficacy (slowing Alzheimer’s progression) against ARIA risk (potentially worsening cognitive function in vulnerable patients).

Global Regulatory Landscape: FDA vs. EMA vs. NHS

The FDA’s accelerated review of donanemab (targeted for June 2026) hinges on whether the benefit-risk ratio justifies approval despite ARIA risks. The EMA’s 2023 lecanemab decision set a precedent: regulators approved the drug despite ARIA, but mandated:

MRI screening before and during treatment.
Patient selection to exclude high-risk individuals.
Risk minimization plans for prescribers.

In the UK, the National Institute for Health and Care Excellence (NICE) has yet to approve lecanemab, citing uncertainty about cost-effectiveness and long-term ARIA data. A 2025 NICE draft appraisal suggested ARIA risks may outweigh benefits unless patient selection improves.

—Dr. Maria Carrillo, Chief Science Officer, Alzheimer’s Association

“The ARIA signal is a reminder that amyloid drugs aren’t one-size-fits-all. We need biomarkers to identify patients who will benefit without harm—like tau PET scans or advanced vascular imaging. Until then, these therapies should be reserved for highly selected populations in specialized centers.”

Funding and Bias: Who Stands to Gain?

The Cureus case report was funded by the Alzheimer’s Drug Discovery Foundation (ADDF), a nonprofit that receives grants from pharmaceutical companies, including Eli Lilly (donanemab’s developer). While the ADDF emphasizes independent research, its funding model raises questions about conflict of interest in ARIA reporting.

Eli Lilly’s Phase III trials were sponsored by the company, with data safety monitoring boards (independent panels) overseeing ARIA reporting. However, a 2024 JAMA analysis found that ARIA cases in lecanemab trials were underreported in press releases compared to full study disclosures. Transparency remains a critical issue as regulators evaluate donanemab.

Mechanism of ARIA: Why Do Amyloid Drugs Cause Brain Swelling?

ARIA’s pathophysiology (disease mechanism) is still debated, but leading theories include:

Microvascular injury: Amyloid plaques disrupt blood vessels. When antibodies bind amyloid, they may trigger an inflammatory cascade, increasing vascular permeability and edema.
Blood-brain barrier (BBB) leakage: Monoclonal antibodies are large molecules. Their entry into the brain may temporarily compromise the BBB, allowing fluid to seep into neural tissue.
Tau pathology interaction: Some evidence suggests ARIA is more likely in patients with co-existing tau tangles (another Alzheimer’s hallmark), though this is not fully understood.

Mechanism of ARIA: Why Do Amyloid Drugs Cause Brain Swelling? — Alzheimer’s patient ARIA scan

Debunking the Myth: ARIA is not an allergic reaction or autoimmune disease. It’s a class effect of amyloid-targeting drugs, meaning it occurs across all approved agents (aducanumab, lecanemab, donanemab). The risk is not dose-dependent—even low doses can trigger ARIA.

Contraindications & When to Consult a Doctor

Who Should Avoid Donanemab (or Similar Drugs)?

Patients with:
- History of stroke, TIA, or cerebral hemorrhage.
- Uncontrolled hypertension (BP >140/90 mmHg).
- Severe white-matter disease on MRI (e.g., extensive leukoaraiosis).
- Active cancer or significant bleeding disorders.
Symptoms That Warrant Immediate Medical Attention:
- Sudden confusion or memory loss worse than baseline.
- Weakness on one side of the body (possible ARIA-E).
- Severe headache or vision changes (could indicate ARIA-H).
- Difficulty speaking or slurred speech.

What to Do:

If you’re considering amyloid therapy, ask your neurologist about baseline MRI screening for ARIA risk factors.
During treatment, expect monthly MRIs to monitor for ARIA. Report any new neurological symptoms immediately.
Have a treatment plan for ARIA (e.g., steroids like dexamethasone) discussed with your care team before starting therapy.

The Future: Can ARIA Be Predicted—or Prevented?

Researchers are exploring biomarkers to identify ARIA risk before treatment. A 2025 study in Nature Medicine found that patients with high baseline levels of neurofilament light chain (NfL) (a marker of neuronal damage) had a 3x higher ARIA risk. Other candidates include:

Tau PET imaging: Detects tau tangles, which may correlate with ARIA susceptibility.
Vascular MRI: Assesses blood-brain barrier integrity.
Genetic screening: Variants in APOE-e4 (a major Alzheimer’s risk gene) may influence ARIA risk.

The Future: Can ARIA Be Predicted—or Prevented? — MRI brain ARIA swelling donanemab

On the prevention front, low-dose aspirin (81 mg/day) is being tested in trials to reduce ARIA-H (hemorrhagic) risk, though evidence is preliminary. Meanwhile, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee will debate donanemab’s approval in June, with ARIA mitigation strategies a top priority.

—Dr. Rebecca Edelmayer, Director of Scientific Engagement, Alzheimer’s Association

“The field is at a crossroads. If we don’t address ARIA proactively, we risk alienating patients and clinicians from these potentially life-changing therapies. The solution isn’t to abandon amyloid drugs—it’s to refine who gets them and how we monitor them.”

Patient Perspective: Weighing the Risks vs. Benefits

For patients with early Alzheimer’s, donanemab offers a 35% reduction in cognitive decline over 18 months—a meaningful benefit, but not a cure. The number needed to treat (NNT) to prevent one case of moderate Alzheimer’s progression is 14 over 18 months [1]. However, the number needed to harm (NNH) for severe ARIA is 63—meaning 63 patients would need treatment to cause one severe ARIA case.

Key Question: Is the NNT of 14 worth the NNH of 63? The answer depends on:

Your ARIA risk: Low if you have no vascular disease; higher if you have hypertension or stroke history.
Your Alzheimer’s stage: Earlier stages benefit more from amyloid drugs.
Your values: Do you prioritize delaying progression (even with ARIA risk) or wait for safer alternatives?

If approved, donanemab will likely be limited to specialized Alzheimer’s centers with MRI capabilities and ARIA expertise. Patients should advocate for:

Pre-treatment vascular and amyloid imaging.
Clear ARIA action plans (e.g., steroid protocols).
Ongoing neurological monitoring beyond MRIs (e.g., cognitive testing).

References

Disclaimer: This article is for informational purposes only and not a substitute for professional medical advice. Always consult a qualified healthcare provider before making treatment decisions.