Summary: For years, brain swelling has been the most feared side effect of the newest generation of Alzheimer’s drugs like lecanemab and donanemab. Known as ARIA-E (amyloid-related imaging abnormality with edema), this swelling usually prompts doctors to pause or slow down treatment. However, a groundbreaking new study suggests that this “adverse event” might actually be a sign the drug is winning.
By analyzing PET scans of patients who experienced moderate to severe swelling, researchers found that the areas of the brain that swelled actually showed a significantly larger decrease in amyloid plaques compared to areas that didn’t. This suggests that ARIA-E, while requiring careful management, acts as a geographic marker for where the treatment is hitting the disease the hardest.
Key Facts
- The Efficacy Signal: In 80% of patients studied, brain regions that experienced ARIA-E (swelling) showed a more substantial clearing of toxic amyloid plaques.
- A “Front Lines” Marker: Joseph Masdeu, MD, PhD, suggests ARIA-E should be reframed as a potential indicator of high local treatment activity rather than just a medical error.
- Vascular Permeability: The swelling likely occurs because the drugs make local blood vessels more permeable, allowing a higher concentration of the medication to reach and dissolve the amyloid clumps.
- The Immune Response: The inflammation may be the physical result of microglia (immune cells) aggressively “gobbling up” amyloid in those specific regions.
- The APOE Factor: All participants in the study were APOE ε4 carriers, who are both at higher risk for Alzheimer’s and more prone to developing ARIA side effects.
Source: Houston Methodist
A new Alzheimer’s treatment side effect that results in brain swelling may have an upside, according to a new study from Houston Methodist Research Institute.
The research finds that beta amyloid – a protein that accumulates as plaques in the brain – may be cleared more in brain regions that had this side effect, signaling a stronger treatment response.
Led by Joseph Masdeu, M.D., Ph.D., director of the Nantz National Alzheimer Center and Neuroimaging and recently published in the American Journal of Neuroradiology, the research examined Alzheimer’s patients who had moderate or severe amyloid-related imaging abnormality edema (ARIA-E), a side effect of treatment that causes leakage of plasma from the blood into some regions of the brain and results in swelling.
The researchers compared scans taken before and after the swelling had receded. Among most patients, areas that had swelling showed larger drops in brain plaques than areas that never swelled.
“This study shows that not all parts of the brain respond equally to anti‑amyloid therapy,” Masdeu, professor of Neurology in the Department of Neurology at Houston Methodist Research Institute said.
“For the first time, results show that the brain regions that swell during treatment have a greater decrease in the amyloid signal on Positron emission tomography (PET) Scan, possibly because more amyloid is removed or because amyloid is hidden on PET. That reframes ARIA‑E from being only a side effect to a possible sign of strong local treatment activity.”
Clinically, this side effect is managed in a straightforward way: when swelling appears, clinicians typically slow or briefly pause treatment and monitor the patient closely. In most cases, the swelling then recedes and disappears, after which treatment can be resumed as appropriate.
These new findings offer doctors and families a more nuanced way to interpret this side effect, balancing safety with the possibility that it may coincide with a stronger local treatment response.
About 6.9 million Americans are living with Alzheimer’s and the number is set to double to 14 million by 2060, according to the Centers for Disease Control and Prevention.
The investigators are expanding the patient sample and will collaborate with other institutions, including the Longitudinal Early Onset Alzheimer’s Disease Study (LEADS) consortium, to validate the results in larger, more diverse cohorts.
Other collaborators on the study are Quentin Finn and Belen Pascual from Houston Methodist and Paul Schulz from UTHealth Houston.
Funding: This study was funded by the Cho, Farish Graham, Harrison and Nantz Funds from the Houston Methodist Foundation. The florbetaben PET scans for Patient 1 were funded by the National Institutes of Health through the LEADS Consortium, funded by the National Institute on Aging.
Key Questions Answered:
A: It’s a “productive” side effect. While it still requires a treatment pause to ensure patient safety, the study suggests that the swelling is the sound of the brain’s “cleanup crew” in overdrive.
A: Brains are complex; some regions have denser plaque buildup or more reactive blood vessels. The drug seems to trigger a “storm” of activity in these high-response zones, leading to both the swelling and the superior plaque removal.
A: Possibly. If ARIA-E is indeed a marker of high drug activity, it could eventually help doctors identify which patients are responding most aggressively to the therapy.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
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) positron emission tomography (PET) signal reduction is unknown.
MATERIALS AND METHODS: In patients with moderate or severe ARIA-E, we quantified changes in Aβ PET signal before and after ARIA-E resolution, comparing regions affected by ARIA-E with unaffected regions.
RESULTS: In four of five patients treated with lecanemab or donanemab and who had 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 areas affected by ARIA-E may reflect enhanced local Aβ clearance, reduced tracer binding site availability, impaired glymphatic flow from immune complex deposition, or other mechanisms. The finding of greater regional Aβ PET signal reduction in ARIA-E regions refines the characterization of ARIA-E and raises the possibility that its occurrence may have beneficial as well as adverse implications.
