Experimental Alzheimer's drug shows promise by targeting tau protein

For two decades, Alzheimer's researchers have watched amyloid protein accumulate in the brain like snow gathering on a roof—silent, invisible, years before the first symptom appears. Two drugs now on the market, lecanemab and donanemab, try to sweep that buildup away, and they work, but only modestly. They slow the mind's decline. They do not stop it. On Tuesday, researchers presented findings from a different approach entirely: a drug that doesn't attack the protein already there, but instead tells the brain to make less of it in the first place.

The drug is called diranersen, made by Biogen. It targets tau, the second villain in Alzheimer's toxic partnership with amyloid. Scientists have long suspected that amyloid triggers tau to misfold and tangle inside neurons, setting off the cascade that erases memory and thought. But developing drugs to fight tau has been a graveyard of failed attempts. This time, something worked. In a study of roughly 400 people with mild cognitive impairment or early Alzheimer's, diranersen slowed cognitive decline in five of six different brain tests. In one measure, the lowest dose—given twice a year as a shot into the fluid around the spinal cord—reduced cognitive decline by 26 percent, a figure researchers said was approximately equivalent to what amyloid drugs achieve.

The result was unexpected in a crucial way. Biogen had designed the study to show that higher doses would work better than lower ones. They didn't. The lowest dose proved most effective, which meant the trial technically failed to meet its primary goal. Yet the finding was encouraging enough that Biogen is moving forward with a larger study to confirm the benefit. "This is really quite promising if it were to hold up," said Jessica Langbaum of the Banner Alzheimer's Institute in Phoenix, who was not part of the research. Dr. Reisa Sperling of Mass General Brigham, also uninvolved, offered a more cautious reading: "This is early days. But I think it will reinvigorate interest and investment in lots of tau mechanisms, and the field needs that."

Diranersen works through a mechanism called antisense oligonucleotide therapy. Rather than trying to clear tau that has already accumulated and tangled, the drug instructs the gene that produces tau to make less of it. The logic is straightforward: if you reduce tau production, you reduce the burden on the brain's own cleanup systems, allowing them to clear what tau does form more efficiently. The drug is delivered directly into the cerebrospinal fluid via spinal injection, a more direct route to the brain than the intravenous infusions used for amyloid drugs. Side effects were manageable—injection site pain and temporary confusion lasting about a week—with no signs of brain inflammation, a concern that has shadowed some amyloid treatments.

The tau field is suddenly crowded with new approaches. The University of California, San Francisco, last week opened the Alzheimer's Tau Platform, a National Institutes of Health-funded study that will test multiple experimental tau therapies, some alone and some combined 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. The platform will expand to sites across the country and eventually include people who carry Alzheimer's-related proteins but have no symptoms yet.

Other researchers are pursuing tau through unexpected angles. An experimental cholesterol drug called obicetrapib, developed by NewAmsterdam Pharma, might do double duty for people carrying the APOE4 gene, which increases Alzheimer's risk and also affects how the body processes cholesterol. The company plans to test whether lowering cholesterol in these high-risk individuals also reduces Alzheimer's protein buildup. Meanwhile, Denali Therapeutics is working on a technology that uses iron—which naturally crosses into the brain—as a transport vehicle to deliver tau and amyloid-targeting drugs more efficiently across the blood-brain barrier.

Alzheimer's affects more than 7 million Americans and tens of millions worldwide. It remains the leading cause of dementia, and its underlying biology is still not fully understood. Amyloid begins accumulating decades before symptoms appear, but amyloid alone does not cause the disease. The emerging consensus is that amyloid sets the stage, triggering tau to misfold and propagate through the brain in tangles that destroy neurons. If diranersen's promise holds in larger trials, it would represent a fundamentally different way to intervene—not by cleaning up the mess, but by preventing so much mess from being made in the first place.