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.

Scientists at the University of New Mexico and University of Tennessee have discovered that the brain enzyme OTULIN plays an unexpected role as a master regulator of tau protein production and RNA metabolism in neurons. While investigating how to clear toxic tau tangles characteristic of Alzheimer's disease, researchers found that eliminating OTULIN caused tau to disappear completely—not through enhanced degradation, but by preventing its gene from being expressed. The study, published in Genomic Psychiatry, revealed that when OTULIN was knocked out in neuroblastoma cells, it triggered massive changes in gene expression (13,341 genes downregulated, 774 upregulated) and fundamentally altered how neurons process RNA. Comparing Alzheimer's patient neurons to healthy controls showed over 4,500 differentially expressed genes. Partial inhibition of OTULIN with a novel compound (UC495) reduced pathological tau in Alzheimer's patient neurons without complete elimination, suggesting a therapeutic window exists. This paradigm-shifting discovery identifies OTULIN as a potential drug target for Alzheimer's and related dementias, though researchers emphasize the need for careful modulation rather than complete inhibition. The findings also illuminate previously unknown connections between protein quality control systems, RNA metabolism, and neurodegenerative disease.