Scientists Finally Crack How the Leading Alzheimer's Drug Works — And the Answer Points to Better Treatments

Scientists at KU Leuven and the Flemish Institute for Biotechnology have solved a mystery that has puzzled neurologists since lecanemab received FDA approval in 2023: exactly how does the drug work at the cellular level? The answer, published in Nature Neuroscience and led by Professor Bart De Strooper with co-first authors Dr. Giulia Albertini and Magdalena Zielonka, fundamentally reframes understanding of amyloid immunotherapy and points toward next-generation Alzheimer's treatments that could be more targeted, effective, and free from the brain-swelling side effects that currently limit lecanemab's clinical use.

The research team discovered that lecanemab's therapeutic action does not primarily come from the antibody binding to amyloid-beta plaques, as had long been assumed. Instead, a specific structural region of the antibody called the Fc fragment — the end of the Y-shaped antibody molecule opposite from its binding tips — drives the drug's effectiveness. The Fc fragment acts as an anchor that brain immune cells called microglia latch onto, triggering the cells to mount a sustained attack on amyloid deposits. When the researchers created a version of lecanemab with the Fc fragment removed, the antibody still bound to plaques but lost virtually all its therapeutic effect, demonstrating that immune cell activation rather than direct plaque binding is the mechanism that actually works.

Using single-cell RNA sequencing and spatial transcriptomic analyses on human microglia transplanted into mouse models, the team identified the specific genetic program that microglia activate in response to lecanemab treatment — a cascade of gene expression changes that enhances phagocytosis, lysosomal degradation of consumed material, metabolic reprogramming to support this intensive activity, and immune signaling. The researchers also identified a specific protein called SPP1, or osteopontin, as a key driver of successful amyloid clearance under lecanemab treatment. This detailed molecular map of what happens inside microglia during effective therapy provides the field with a precise blueprint for developing better drugs.

The discovery has major implications for drug development. If the Fc fragment — and the microglial activation it triggers — is the critical therapeutic element, developers can now design drugs that bypass the amyloid-binding step entirely and directly engage microglia through other mechanisms. This could potentially produce more powerful amyloid-clearing effects while reducing the side effects currently associated with lecanemab, particularly amyloid-related imaging abnormalities — a form of brain swelling or microhemorrhage that affects a significant fraction of patients and occasionally requires them to discontinue treatment. Several pharmaceutical companies are already pursuing direct microglia-activating strategies in their Alzheimer's pipelines, and the new mechanistic clarity from the KU Leuven team provides a framework for validating and optimizing those approaches.

Lecanemab, marketed as Leqembi and jointly developed by Eisai and Biogen, is currently the most effective disease-modifying Alzheimer's therapy approved by the FDA, having demonstrated in clinical trials a roughly 27 percent slowing of cognitive decline compared to placebo. Despite its approval, patient access has been limited by high costs — approximately $26,500 per year — as well as the monitoring burden associated with detecting amyloid-related imaging abnormalities through regular MRI scans. Understanding the drug's mechanism more precisely opens multiple paths toward more affordable, accessible, or effective treatments that might eventually benefit the estimated 7 million Americans and 50 million people worldwide living with Alzheimer's disease and related dementias. Alzheimer's research organizations called the mechanism discovery 'a turning point' in the field, saying it transforms what had been an empirical therapy into one with a well-understood molecular rationale.