Experimental Alzheimer's drug shows promise targeting tau protein in new study

Researchers announced Tuesday that an experimental drug called diranersen might slow the progression of early Alzheimer's disease through a mechanism entirely different from the treatments currently available. Rather than attacking the amyloid protein that accumulates in the brains of Alzheimer's patients, diranersen targets tau, the other major protein implicated in the disease's progression. The finding represents a significant shift in how scientists are thinking about treating one of the world's most devastating neurodegenerative conditions.

Alzheimer's disease affects more than 7 million Americans and tens of millions of people worldwide. For decades, researchers believed amyloid buildup was the primary culprit, and two drugs approved in recent years—lecanemab and donanemab—attempt to clear amyloid from the brain. But amyloid alone doesn't cause Alzheimer's. The leading theory holds that amyloid accumulation, which begins roughly two decades before symptoms appear, eventually triggers tau to misfold and form tangles inside neurons. These tangles are thought to be what actually triggers cognitive decline. Previous attempts to develop drugs targeting tau have largely failed, making diranersen's results noteworthy.

Biogen and its partner Ionis Pharmaceuticals tested diranersen in a study of roughly 400 people with mild cognitive impairment or mild Alzheimer's disease. The drug works through an unusual mechanism: rather than attacking tau that's already accumulated in the brain, it instructs the gene that produces tau to make less of the protein in the first place. This approach is fundamentally different from amyloid-targeting drugs, which try to clear existing plaques. By reducing tau production, the theory goes, the brain's natural cleanup systems can more easily manage what tau remains. The drug is delivered by injection directly into the fluid surrounding the spinal cord—a more direct route to the brain than the intravenous infusions used for amyloid drugs.

The study produced surprising and somewhat contradictory results. Biogen announced in May that the lowest dose, given twice yearly, showed the strongest effect—a counterintuitive finding that meant the trial failed to meet its primary goal of demonstrating that higher doses produced better outcomes. Yet when researchers examined the actual cognitive effects, the picture looked more encouraging. In five of six different brain tests measuring memory and other cognitive abilities, people who received diranersen showed slower decline than those given placebo. In one test of the lowest dose group, cognitive decline slowed by 26 percent—a reduction roughly equivalent to what amyloid-targeting drugs have achieved in earlier trials. Dr. Cath Mummery of University College London, who led the study, presented these findings at the Alzheimer's Association International Conference in London.

Side effects were generally mild. Patients reported pain at the injection site and temporary confusion that could appear a few days after the shot and last about a week. Importantly, there were no signs of brain inflammation, a complication that can occur with amyloid-targeting drugs. The results are preliminary enough that Biogen is planning a larger study to confirm whether the drug's benefits hold up under more rigorous testing. Jessica Langbaum of the Banner Alzheimer's Institute, who was not involved in the research, called the findings "really quite promising if it were to hold up" in future trials. Dr. Reisa Sperling of Mass General Brigham cautioned that "this is early days," but suggested the work could "reinvigorate interest and investment in lots of tau mechanisms, and the field needs that."

Diranersen is not alone. The University of California, San Francisco, recently launched the Alzheimer's Tau Platform, a first-of-its-kind study funded by the National Institutes of Health that will test multiple experimental anti-tau therapies, both alone and in combination with existing amyloid drugs. The first candidate is a vaccine called AADvac1, designed to train the immune system to recognize and attack a specific problematic form of tau. Researchers are also exploring whether an experimental cholesterol-lowering drug called obicetrapib might offer dual benefits for people at genetic risk of Alzheimer's, since the gene that increases Alzheimer's risk also affects cholesterol metabolism. Other companies are developing new technologies to help drugs cross the blood-brain barrier more efficiently, essentially creating molecular "transport vehicles" that can carry tau and amyloid-targeting drugs deeper into brain tissue.

The convergence of these approaches signals a fundamental shift in Alzheimer's research. For years, the field was dominated by the amyloid hypothesis—the idea that clearing amyloid plaques would stop the disease. That strategy has produced modest benefits, but the results have been underwhelming for many patients. Now, with multiple tau-targeting approaches advancing simultaneously, researchers are betting that attacking the disease from a different angle, or from multiple angles at once, might yield better outcomes. The next few years will determine whether diranersen and its competitors can deliver on that promise.