An experimental drug, diranersen, is showing early promise in slowing cognitive decline associated with Alzheimer's disease by a novel mechanism: reducing the production of the tau protein in the brain. This approach differs from current treatments that target amyloid plaques, another key protein implicated in the disease.
Researchers presented findings at the Alzheimer's Association International Conference in London from a study involving approximately 400 participants. The study indicated that diranersen not only lowered tau levels but also showed signs of slowing cognitive decline. In a small subset of participants, this slowing was comparable to the effects observed with amyloid-targeting therapies.
Tau is one of two toxic proteins central to Alzheimer's progression. While prior efforts to develop drugs that directly clear tau buildup have been unsuccessful, diranersen functions differently. It is an antisense oligonucleotide that instructs a gene responsible for tau production to generate less of the protein. Dr. Cath Mummery of University College London, who led the study, explained that by lowering tau production, the brain's natural clearance mechanisms have a better capacity to manage the abnormal tau forms.
Two existing Alzheimer's drugs, lecanemab and donanemab, work by clearing amyloid buildup and offer modest slowing of cognitive decline. These are administered through infusions or injections. Diranersen, however, is injected into the fluid surrounding the spinal cord, providing a more direct route to the brain.
Biogen, the developer of diranersen, reported in May that the lowest dose, administered every six months, showed the most significant effect, which was an unexpected outcome. Despite this, further analysis of the study data revealed that participants receiving diranersen experienced slower cognitive decline compared to those on a placebo. Across five of six cognitive tests, the lowest dose demonstrated a 26% reduction in cognitive decline, a change noted to be similar to that seen with amyloid drugs.
Side effects of diranersen included pain at the injection site and a temporary state of confusion that typically resolved within a week. Importantly, the drug did not show signs of brain inflammation, a potential side effect associated with some anti-amyloid therapies.
Biogen is planning a larger study to further validate these findings. Experts not involved in the study, such as Jessica Langbaum of the Banner Alzheimer's Institute, described the results as "promising if it were to hold up" in future testing. Dr. Reisa Sperling of Mass General Brigham noted that while "early days," these findings could "reinvigorate interest and investment in lots of tau mechanisms."
This research is part of a broader effort to combat Alzheimer's disease through novel strategies. Other approaches under investigation include a tau vaccine, the repurposing of a heart drug for individuals at high risk of Alzheimer's, and methods to enhance drug delivery across the blood-brain barrier. The University of California, San Francisco, has launched a study to test various anti-tau therapies, including a vaccine called AADvac1, in combination with existing amyloid treatments. Additionally, researchers are exploring whether cholesterol-lowering drugs might play a role in reducing Alzheimer's-related protein buildup, particularly in individuals with a genetic predisposition.