Literature Review

How does lecanemab work in Alzheimer’s?



Lecanemab (Lequembi, Esai), an amyloid-beta–directed antibody therapy, is approved by the Food and Drug Administration for the treatment of Alzheimer’s disease (AD). But exactly how the drug clears amyloid-beta wasn’t clear.

Now new research suggests the drug, which was approved by the FDA in January, targets a particular molecular cascade, the plasma contact system, which drives amyloid-beta toxicity.

The investigators tested the effectiveness of various forms of amyloid-beta in activating the plasma contact system and found that amyloid-beta protofibrils, known to be the most toxic form of amyloid-beta, promoted the activation of this molecular cascade and that lecanemab inhibited pathway activation.

“In our study, we looked at lecanemab and found it can block the activation of the contact system, which could be one of the reasons that it works so well for AD,” study coinvestigator Erin Norris, PhD, research associate professor, Rockefeller University, New York, said in an interview.

The study was published online in the Proceedings of the National Academy of Science.

Unknown mechanism

“Many years ago, we started looking at the involvement of vascular dysfunction in AD,” Dr. Norris said. “We wanted to see whether or not irregular blood clotting or problems with blood flow was problematic in Alzheimer’s patients.”

The researchers found that fibrin, a major component involved in blood clotting, can extravasate into the brain.

“The blood-brain barrier can break down in Alzheimer’s, so things from the blood can move into the brain and deposit there,” she added. Fibrin then interacts with amyloid-beta, the major pathogenic protein in AD.

Dr. Norris explained that fibrin clots can form in two different ways. One is through the normal process that occurs when there’s an injury and bleeding. The second is through intrinsic clotting, which takes place through the contact system.

“We started looking into this system and found that the plasma of Alzheimer’s patients showed irregular levels of these enzymes and proteins that are part of the intrinsic clotting system compared to those of normal controls,” said Dr. Norris.

“This paper was an extension of years studying this pathway and these mechanisms. It was also inspired by the approval of lecanemab and its release for use in Alzheimer’s patients,” she added.

In previous research, the same researchers found that amyloid-beta has different forms. “It’s normally soluble, and it’s a very tiny molecule,” Dr. Norris said. “But over time, and in different situations, it can start to aggregate, becoming bigger and bigger.”

Implications beyond Alzheimer’s

Postmortem tissue analysis has found fibrillar plaques that are “clumped together.” These are insoluble and hard to get rid of, she said. “Protofibrils are the step before amyloid-beta forms fibrils and are considered to be the most toxic form, although the mechanism behind why it’s so toxic is not understood.”

Previous research has already shown that amyloid-beta can activate the contact system. The contact system has two “arms,” the first of which is involved with clotting, and the second with inflammation, Dr. Norris said. In fact, it’s the plasma contact system that links vascular and inflammatory pathways.

The plasma contact system leads to the clotting of fibrin, Dr. Norris continued. It activates factor XII, which leads to blood clotting by binding to coagulation factor XI.

The contact system also causes inflammation – the second “arm.” Bradykinin, a potent inflammatory molecule, is released by binding to high-molecular-weight kininogen (HK). In addition to inflammation, bradykinin can cause edema and blood-brain barrier permeability.

Although it’s been known that amyloid-beta can activate the contact system, the particular form of amyloid-beta implicated in this cascade has not been identified. And so, the researchers incubated amyloid-beta42 with human plasma, testing various types of amyloid-beta – monomers, oligomers, protofibrils, and fibrils – to see which would activate the contact system.

Amyloid-beta protofibrils promoted the activation of the contact system, as evidenced by several reactions, including activation of factor XII, while other forms of amyloid-beta did not. HK also “bound tightly” to amyloid-beta protofibrils, with “weaker” binding to other amyloid-beta species, the authors reported, confirming that amyloid-beta protofibrils bind to HK and factor XII.

Bradykinin levels were increased by amyloid-beta protofibrils, which also induced faster clotting, compared with other forms of amyloid-beta.

The researchers introduced lecanemab into the picture and found it “dramatically inhibited” contact system activation induced by amyloid-beta protofibrils. For example, it blocked the binding of factor XII to amyloid-beta. By contrast, human IgG (which the researchers used as a control) had no effect.

Additionally, lecanemab also prevented accelerated intrinsic coagulation in normal human plasma mediated by amyloid-beta protofibril.

Senior author Sidney Strickland, PhD, the Zachary and Elizabeth M. Fisher professor in Alzheimer’s and neurodegenerative disease, Rockefeller University, said in an interview: “One of the strong motivators for conducting this study was the fact that this drug, which is effective in AD, targets this specific form of amyloid-beta; but no one knows why it›s more toxic. We thought we could see if we could tie it to what we›re working on, and we found it ties in beautifully.”

The findings have implications that go beyond AD, Dr. Strickland said. “The contact system is implicated in lots of different pathologies, including sickle cell anemia, sepsis, inflammatory bowel disease, and so on.” Blocking the contact system might be a helpful approach in these conditions too.


Recommended Reading

Long COVID ‘brain fog’ confounds doctors, but new research offers hope
Federal Practitioner
U.S. states, counties with highest Alzheimer’s prevalence rates identified
Federal Practitioner
Cognitive benefit of highly touted MIND diet questioned
Federal Practitioner
New Alzheimer’s drugs: Setting realistic expectations
Federal Practitioner
Inhaling pleasant scents during sleep tied to a dramatic boost in cognition
Federal Practitioner
Which factors distinguish superagers from the rest of us?
Federal Practitioner
Few meet eligibility for newer Alzheimer’s drugs
Federal Practitioner
Dementia diagnosis a good time to reduce polypharmacy
Federal Practitioner
Abdominal fat linked to lower brain volume in midlife
Federal Practitioner
Sedentary lifestyle tied to increased dementia risk
Federal Practitioner