Study elucidates how anti-amyloid antibody therapy lecanemab works in Alzheimer's disease

Lecanemab, sold under the name Leqembi, is a monoclonal antibody therapy for Alzheimer's disease that clears toxic amyloid plaques and delays cognitive decline. Researchers from VIB and KU Leuven have now demonstrated the mechanism behind it for the first time. They showed that the 'Fc fragment' of this monoclonal antibody is essential for engaging microglia - the immune cells of the brain -, thus initiating the cellular machinery needed for plaque removal. This is the first direct mechanistic explanation for how this class of therapies works. It clarifies uncertainties in the field and offers a blueprint for developing safer, more effective Alzheimer's treatments. The findings are published in Nature Neuroscience.

Our study is the first to clearly demonstrate how this anti-amyloid antibody therapy works in Alzheimer's disease. We show that the therapy's efficacy relies on the antibody's Fc fragment, which activates microglia to effectively clear amyloid plaques. The Fc fragment works as an anchor that microglia latch onto when they are near plaques, as a consequence of which these cells are reprogrammed to clear plaques more efficiently."

Dr. Giulia Albertini, co-first author of the study

Alzheimer's disease affects over 55 million people and is caused by the onset of amyloid plaques in the brain, toxic protein agglomerates that ultimately cause neuronal death and eventually dementia. Microglia, the brain's immune cells, naturally gather around these plaques, but they fail to clear them as part of their immune function. In recent years, therapies have been developed that focus on restoring this critical microglial function.

Antibody therapy restoring microglial function

Lecanemab, already FDA-approved, is one such anti-amyloid antibody therapy designed to target amyloid-beta plaques and slow down the progression of Alzheimer's disease. However, associated side-effects have compromised its efficacy, and little is known about how this antibody is able to clear the toxic aggregates.

Typically, an antibody consists of two regions that work together. One region is responsible for recognizing and binding a specific target (i.e., the amyloid plaques), while the other region, the Fc fragment, signals the immune system. Previous studies had suggested that plaque clearance is mediated by activation of microglia, but direct experimental evidence linking microglia activity to the therapeutic efficacy of Lecanemab was lacking. Besides, alternative Fc-independent mechanisms of plaque removal have also been widely proposed. The team led by Prof. Bart De Strooper showed that the Fc fragment is essential, since microglia only responded to the antibody when this part was functional.

Using an in-house Alzheimer's mouse model engrafted with human microglial cells, the researchers created a controlled system in which they could examine how lecanemab activates human cells and how this leads to amyloid plaque clearance. The researchers also found that an antibody without the Fc fragment had no effect.

"The fact that we used human microglia within a controlled experimental model was a major strength of our study. This allowed us to test the very antibodies used in patients and observe human-specific responses with unprecedented resolution", adds Magdalena Zielonka, co-first author.

The cellular processes of microglial clearance

The researchers then proceeded to elucidate how microglia clean the amyloid plaques in this hybrid human-animal model following lecanemab activation. They identified key cellular machinery needed to clear the amyloid plaques: namely, phagocytosis and lysosomal activity. Without the Fc fragment, none of these critical cellular processes were triggered. By combining single-cell and spatial transcriptomics with the available expertise at the VIB-KU Leuven Center for Brain & Disease Research, the team uncovered a microglial gene program, marked by strong expression of the gene SPP1. This was made possible by using NOVA-ST, a technique developed by the Stein Aerts lab (VIB-KU Leuven).

The findings of the VIB-KU Leuven research team pave the way for more refined Alzheimer's therapies by defining the specific microglial program that drives effective plaque clearance.

"This opens doors to future therapies that may activate microglia without requiring antibodies. Understanding the importance of the Fc fragment helps guide the design of next-generation Alzheimer's drugs", concludes Prof. Bart De Strooper.

Funding

The research team at the VIB-KU Leuven Center for Brain & Disease Research was financially supported by the European Research Council (ERC), Alzheimer's Association USA, Research Foundation Flanders (FWO), Queen Elisabeth Medical Foundation for Neurosciences, Stichting Alzheimer Onderzoek - Fondation Recherche Alzheimer (STOPALZHEIMER.BE), KU Leuven, VIB, and UK Dementia Research Institute University College London.