In Barcelona's laboratories at the Universitat Autònoma de Barcelona, researchers led by Chair Professor Sandra Villegas have engineered a safer path through one of modern medicine's most promising—and most perilous—breakthroughs in Alzheimer's treatment. The European Medicines Agency's 2025 approval of two groundbreaking antibodies, lecanemab and donanemab, marked a historic turning point for a disease that has long resisted effective treatment. Yet these same drugs carry a troubling cost: cerebral bleeding, occurring in 10 to 27 percent of patients who receive them.
The tragedy lies not in what these antibodies do, but in how they do it. Both drugs work by targeting amyloid-beta, a protein fragment that accumulates in Alzheimer's patients' brains and fuels cognitive decline. By mobilizing the immune system to eliminate this protein, they achieve something once thought impossible—slowing and even partially reversing the disease's devastating progression. But full-length antibodies carry a fatal flaw: they recruit systemic immune cells into the brain, disrupting the delicate blood-brain barrier and triggering life-threatening hemorrhages. The problem is so severe that current European guidelines restrict these treatments to patients carrying zero or at most one copy of the APOEε4 genetic variant, excluding those at highest risk of the disease itself.
Villegas's team approached this paradox with elegant molecular surgery. Rather than deploy the entire antibody, they created a monocatenary antibody fragment—scFv-h3D6—that retains the disease-fighting capacity while stripping away the region that recruits immune cells into the brain. Working with collaborators Dr. Silvia Lope-Piedrafita, an expert in magnetic resonance imaging, and Dr. Mar Hernández-Guillamon, a specialist in Alzheimer's mouse models, the group tested their hypothesis directly. Using magnetic resonance to visualize brain bleeding in mice, they compared the full-length antibody bapineuzumab against their engineered fragment.
The results, published in Biomolecules in 2025, are strikingly clear: the antibody fragment prevented bleeding entirely while maintaining full therapeutic benefit. Mice treated with the fragment showed the same protection against cognitive decline—demonstrated at molecular, cellular, and behavioral scales—as those receiving full-length antibodies, but without the hemorrhagic damage.
What makes this breakthrough particularly hopeful is its elegance: rather than compromise on efficacy or accept bleeding as an unavoidable price, Villegas's team removed the problem at its source. By redesigning the antibody to do what's necessary and no more, they've created a template for safer immunotherapy across neurodegenerative diseases. "Antibody fragments can offer a safer alternative than intact antibodies, which paves the way for new research into an effective and safe drug for Alzheimer's disease," Villegas explains.
For the millions living with Alzheimer's—and the millions more at genetic risk—this work represents something more than a technical achievement. It opens the door to treating the disease's underlying cause without the fear of catastrophic side effects. The path from Barcelona's laboratories to patients' clinics still requires further development, but the fundamental proof is established: safety and efficacy need not be traded away. Sometimes they can simply be redesigned.