Q&A: The risks of brain bleeds in antibody treatments for Alzheimer’s disease

Ryan Institute Co-Executive Director William Van Nostrand answers questions about the potential risk of brain bleeds associated with newly-approved lecanemab and similar treatments.

This summer, the FDA granted full approval to lecanemab, an antibody treatment for Alzheimer’s disease. 

The antibody—a protein that works by clearing amyloid-beta protein “plaques” in the brain, a signature of Alzheimer’s disease—has been shown to have a modest effect on reducing the rate of decline in memory, cognitive function, and ability to perform daily tasks in people with Alzheimer’s disease. 

Lecanemab is one of three anti-amyloid immunotherapies to show a disease-modifying benefit in Alzheimer’s disease (Biogen and Esai’s aducanumab received accelerated FDA approval last year, and Eli Lilly’s donanemab announced promising results of a Phase 3 clinical study in May). While these findings are encouraging, trial studies have identified a low risk of hemorrhagic stroke with the treatments, a risk that is slightly higher for those on blood thinners and anticoagulants. These findings have raised some concern and the need for more research. 

There is a low risk of hemorrhagic stroke with the treatments, but the study of brain bleeds in another disorder could potentially hold clues on why this risk occurs and how it could be mitigated.
William Van Nostrand, Ryan Institute Co-Executive Director and Herrmann Professor of Neuroscience / Photo by Kathleen Dooher

Ryan Institute for Neuroscience Co-Executive Director William Van Nostrand, a professor of Biomedical and Pharmaceutical Sciences and Herrmann Professor of Neuroscience, is a longtime researcher of cerebral amyloid angiopathy (CAA), a disorder characterized by amyloid accumulation in brain blood vessels that can cause hemorrhages and commonly occurs with Alzheimer’s disease. The study of brain bleeds in CAA could potentially hold clues on why this risk occurs with the antibody amyloid-clearing therapies.  

He explains more about the research needed to understand this risk. 

What is the concern regarding brain bleeds in Alzheimers amyloid immunotherapies such as lecanemab?

The trials for all three immunotherapy drugs have shown some level of risk of developing severe issues regarding bleeds in the brain. The risk level is low––one to two percent, but it is there, so there is a concern from clinicians in regard to understanding which patients may be more susceptible than others. It is important to investigate why this immunotherapy approach is increasing this risk. 

Why are brain bleeds dangerous?

Blood leaking into the brain is toxic. Bleeds can be small microbleeds – it is still unclear how significantly microbleeds impact brain health – or they can be large macrobleeds, such as a hemorrhagic stroke, which can be debilitating or fatal. The amyloid immuotherapies are associated with a risk for the larger bleeds. 

Who seems to be most at risk for brain hemorrhaging with this amyloid immunotherapy?

More research is needed, but it appears that people with a high load of CAA would not be good candidates. CAA is a disorder that is common in people with Alzheimer’s disease, where amyloid accumulates in the small and medium sized blood vessels. Many people have this condition to some extent, but some have a higher burden.

These antibodies target amyloid that accumulates as senile plaques in the brain, which is thought to be a contributor to Alzheimer’s disease. They have proven to be effective at removing these plaque deposits, but it could be that once the amyloid is mobilized, pieces of amyloid migrate to the blood vessels, which are one of the brain’s clearance routes for waste and other toxins. If there is already amyloid accumulating in the blood vessels, it can act as a scaffold and further build up amyloid in the vasculature. 

How do these questions relate to your own work?

We are interested in understanding why certain blood vessels have a propensity to develop CAA while others do not. We use new rat models for CAA generated in my lab to study this disorder. If we see bleeds developing in one region in our rat models, what is different in this region? Or in a region where there is amyloid but no bleeding? It would be highly informative to do this analysis with an immunotherapy drug. 

Do you think the future of these amyloid-targeting immunotherapies is promising, despite potential risks?

These drugs are not cures, but they have shown promise in slowing the rate of cognitive decline and disease progression. The amyloid imaging related abnormalities, such as hemorrhaging, are clearly aligned with the immunotherapy approach, so if we can understand why that is happening, we could see a tandem therapy–for example, a dual approach where an antibody therapy clears the amyloid and another therapy targets the potential bleeds–to mitigate the risk. 

William Van Nostrand is Co-Executive Director of the George & Anne Ryan Institute for Neuroscience at URI, where he is also Herrmann Professor of Neuroscience and a professor of biomedical and pharmaceutical sciences.