Beyond amyloid

When the US Food and Drug Administration approved the first amyloid-β-targeting monoclonal antibody to treat Alzheimer’s disease in 2021, it was a big move—and a controversial one. Regulators advanced aducanumab over the objection of an expert review panel on the grounds that it cleared amyloid plaques from the brains of people with the condition. But the drug had failed to slow cognitive decline in a clinical trial, and more than a third of people in the trial who received it had shown evidence of brain swelling that concerned doctors. Still, patients and advocacy groups rejoiced. Past efforts to intervene in the disease by drugging targets including metabolism, mitochondria, secretases, steroid hormones, and cholesterol had yielded one disappointment after another. Now a disease-modifying drug was available, and more amyloid antibodies were close behind.“For so many years there were so many failures,” says Laura Niesenbaum, executive director of drug development at the Alzheimer’s Drug Discovery Foundation (ADDF), a nonprofit that funds early-stage research into new treatments. “With the monoclonal antibodies targeting amyloid, we got the first breakthrough.” Biogen, the maker of aducanumab, later pulled it from the market to focus on a second drug, which is now one of two such antibodies available in the US. But those also have problems. They delay rather than halt patients’ cognitive decline; they are also costly and carry a risk of severe, sometimes fatal, side effects. As it has become clear that these drugs are no silver bullet for the disease, Niesenbaum says, “the field