Summary: For years, brain swelling has been the most feared complication of the newest anti-amyloid Alzheimer’s therapies, including lecanemab and donanemab. This swelling, known as ARIA-E (amyloid-related imaging abnormality with edema), commonly prompts clinicians to slow or pause treatment. A new study from Houston Methodist Research Institute suggests a different perspective: ARIA-E may mark regions where the drug is most active and effective at clearing amyloid plaques.
Researchers analyzed PET scans from patients who experienced moderate to severe ARIA-E and compared scans taken before the swelling and after it resolved. In most cases, the specific brain regions that developed ARIA-E showed substantially larger reductions in amyloid PET signal than regions that never swelled. These findings indicate that, while ARIA-E requires careful clinical management, it may also serve as a geographic indicator of strong local therapeutic activity.
Key Facts
- Clearer signal of efficacy: In four of five patients studied (80%), brain regions affected by ARIA-E showed greater clearance of amyloid plaques on PET imaging than unaffected areas.
- Rethinking ARIA-E: Joseph Masdeu, MD, PhD, suggests ARIA-E might be reframed from purely an adverse event to a potential marker of intense local drug action.
- Vascular permeability: The swelling likely reflects increased permeability of local blood vessels, permitting higher concentrations of antibody drugs to reach and dissolve plaque deposits.
- Immune activation: The inflammatory response may reflect microglia and other immune cells actively removing amyloid in the affected regions.
- APOE ε4 status: All participants in the study were carriers of the APOE ε4 allele, a genetic variant associated with higher Alzheimer’s risk and a greater likelihood of developing ARIA.
Source: Houston Methodist
New evidence suggests a potential upside to a known side effect of anti-amyloid therapies
The study, led by Joseph Masdeu, M.D., Ph.D., director of the Nantz National Alzheimer Center and Neuroimaging at Houston Methodist, was published in the American Journal of Neuroradiology. Investigators focused on patients treated with anti-amyloid monoclonal antibodies who developed moderate or severe ARIA-E, a reaction that causes plasma to leak into brain tissue and produces localized swelling.
Using β-amyloid PET imaging, the team quantified amyloid signal before ARIA-E onset and after the edema resolved. Across the majority of participants, regions that had been affected by ARIA-E showed larger reductions in PET signal, consistent with more extensive local amyloid clearance or other local changes that reduce tracer binding.
“This study shows that not all parts of the brain respond equally to anti-amyloid therapy,” said Masdeu. “For the first time, our results demonstrate that regions that swell during treatment often show a greater decrease in amyloid PET signal. That does not mean ARIA-E is harmless, but it does suggest it can be a sign of intense local treatment activity.”
Clinically, ARIA-E continues to be managed cautiously: when swelling is detected, clinicians usually slow or temporarily suspend dosing and closely monitor the patient until the edema resolves. In most cases the swelling subsides and treatment can be resumed as clinically appropriate. These new findings help clinicians and families interpret ARIA-E with more nuance—acknowledging the need for safety while recognizing that the side effect may coincide with regions of stronger therapeutic effect.
Approximately 6.9 million Americans currently live with Alzheimer’s disease, and that number is projected to rise substantially in the coming decades. The investigators plan to expand the patient sample and collaborate with other institutions—including members of the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) consortium—to validate these observations in larger and more diverse cohorts.
Collaborators on the study include Quentin Finn and Belen Pascual from Houston Methodist and Paul Schulz from UTHealth Houston.
Funding: The research was supported by the Cho, Farish Graham, Harrison and Nantz Funds from the Houston Methodist Foundation. Florbetaben PET scans for Patient 1 were supported by the National Institutes of Health through the LEADS consortium and the National Institute on Aging.
Key Questions Answered:
A: Not exactly “good,” but potentially “productive.” ARIA-E still requires prompt clinical management to protect patient safety. The study suggests the swelling often coincides with active local removal of amyloid, indicating a vigorous therapeutic response in those regions.
A: Brains are heterogeneous: plaque density, vascular reactivity, immune cell activity, and local drug penetration vary by region. These factors can lead to “hot spots” where drug effect and resulting inflammation are more pronounced.
A: Possibly. If ARIA-E reliably marks regions of high drug activity, it could become one of several indicators clinicians use to assess and predict therapeutic response. Larger studies are needed to confirm this potential.
Editorial Notes:
- This article was edited by an editor at Neuroscience News.
- The journal paper was reviewed in full by the editorial team.
- Additional context was added by staff to help interpret the findings.
About this Alzheimer’s disease research news
Author: Nathaniel Godwin
Source: Houston Methodist
Contact: Nathaniel Godwin – Houston Methodist
Image: The image is credited to Neuroscience News
Original Research: Open access. “β-amyloid PET signal reduction in prior ARIA-E regions after anti-amyloid therapy for Alzheimer’s disease” by Quentin Finn, Belen Pascual, Paul E. Schulz, and Joseph C. Masdeu. American Journal of Neuroradiology. DOI: 10.3174/ajnr.A9111
Abstract
β-amyloid PET signal reduction in prior ARIA-E regions after anti-amyloid therapy for Alzheimer’s disease
Background and purpose: The relationship between regional brain edema caused by anti-amyloid monoclonal antibodies (ARIA-E) and the degree of regional β-amyloid (Aβ) PET signal reduction has been unclear.
Materials and methods: In patients with moderate or severe ARIA-E, we quantified changes in Aβ PET signal before ARIA-E onset and after its resolution, comparing regions affected by ARIA-E with regions that remained unaffected.
Results: In four of five patients treated with lecanemab or donanemab who developed moderate or severe ARIA-E, Aβ PET signal decreased significantly more in regions that had been involved with ARIA-E.
Conclusions: Greater regional Aβ PET signal reduction in ARIA-E regions may reflect enhanced local Aβ clearance, reduced tracer binding availability, impaired glymphatic flow from immune complex deposition, or other mechanisms. These results refine the characterization of ARIA-E and suggest that its occurrence may carry both adverse and potentially beneficial implications.