Turning the Tide on Tau: Q&A With Gladstone’s Lennart Mucke

Nearly two decades ago, a team of scientists at Gladstone Institutes led by Lennart Mucke, MD, published a landmark study in the journal Science.

They discovered that reducing levels of a brain protein called tau could prevent memory deficits and normalize the lifespan of mice genetically engineered to simulate key aspects of Alzheimer’s disease. At the time, the strategy was highly innovative, departing from the field's dominant focus on targeting amyloid plaques.

Fast forward to May 2026: The pharmaceutical company Biogen announced historic initial results from a phase 2 clinical trial testing a new drug called diranersen. The potential treatment acts like a brake on gene expression, stopping the production of tau at its source. The Alzheimer’s Association called it “important progress,” as it’s the first study in humans to successfully lower tau levels in brain, demonstrating the intervention is well tolerated and may slow memory loss and cognitive decline in early-stage Alzheimer's.

Even though the study didn't hit its strict technical target of proving that larger doses automatically work better, patients across the board seem to have experienced a meaningful slowing of mental decline. In fact, the lowest dose tested apparently showed some of the most promising results.

Ahead of the major international Alzheimer’s conference in mid-July, where the full data will be unveiled, we sat down with Mucke, director of the Gladstone Institute of Neurological Disease, to discuss why this moment has been 20 years in the making.

First, for those who might not be familiar with the biology of the brain, what exactly is tau, and why has it become such a critical target in the fight against Alzheimer’s?

Tau is a protein that is normally produced in healthy brains by neurons and other brain cells. It interacts with the internal skeleton of these cells and seems to regulate a number of biochemical processes.

In Alzheimer’s disease, tau becomes structurally altered. It detaches from its normal positions, undergoes abnormal chemical changes, and begins sticking together to form aggregates known as tangles.

However, it remains unclear whether tau promotes cognitive decline through tangle formation or by allowing other factors—such as amyloid proteins or inflammation—to cause abnormal brain activity. These possibilities are not mutually exclusive and, importantly, can both be addressed by reducing overall tau levels in the brain.

In 2007, your lab discovered that reducing tau levels had a striking therapeutic effect in mouse models with amyloid plaques—a primary hallmark of Alzheimer’s disease. Now that strategy seems to be working in humans. What's it like to see your lab's discovery make the leap from mice to real patients?

Seeing a hypothesis you tested in the lab decades ago transition into a tangible clinical benefit for patients is incredibly rewarding. In 2007, we knew we had identified an extraordinarily powerful strategy, but advancing it from mouse models to human patients was a long and complicated process that was critically enabled by some of my dearest colleagues in academia and industry, particularly at Washington University and Ionis Pharmaceuticals.

Biogen's data confirms in humans the findings we originally made in mouse models, which predicted that tau reduction would be safe and well tolerated—something several other tau experts doubted.

The preliminary efficacy data are also in line with our studies in mouse models, which revealed that even partial reduction of tau could reduce Alzheimer’s disease-related brain dysfunction. This is exciting!

The phase 2 trial missed its primary endpoint regarding dose response, yet Biogen and the broader scientific community are treating these results as a massive win. Can you help explain why this trial is considered a success despite missing that primary marker?

In clinical trials, missing a technical goal can look discouraging at first glance, but you have to dig more deeply into the data. The trial was designed to look for a strict, predictable pattern where higher doses would lead to greater benefits than lower doses. What they actually observed were meaningful benefits across all tested doses—with the most pronounced cognitive benefits occurring at the lowest dose. The therapeutic effect seems to be real, even if it didn't follow the exact pattern the investigators expected.

The bottom line is that this is the first randomized study to successfully show both a reduction in tau pathology and a clinical, cognitive benefit in Alzheimer’s patients. In our field, proving that changing a specific biomarker is actually associated with a beneficial effect on patients’ memory and daily function is the ultimate "proof of concept" many have been searching for. Such results give drugmakers confidence to move forward with further testing and development.

As tau-targeting therapies advance in clinical trials, Lennart Mucke shares optimism about the future of Alzheimer’s treatment.

For a long time, the public and the pharmaceutical industry have focused heavily on amyloid-targeting drugs. Why is targeting tau different, and why is it so vital to the future of treating Alzheimer's?

These strategies are very complementary and probably even interdependent. For example, several amyloid-related problems can be prevented by reducing tau. In other words, these factors “conspire” to impair brain cell functions and survival. And they don’t act alone. Other partners in crime include inflammatory factors, as well as the gene APOE4, the most important genetic risk factor for Alzheimer’s. But tau is clearly a central player in this story, forming enabling links among several of the causal factors that increase risk and promote the progression of Alzheimer’s. Therefore, targeting tau could disrupt this entire disease-promoting network.

Looking ahead to the Alzheimer’s Association International Conference in July, what specific details are you eager to see when the full data is released?

For this and all other treatment strategies, I’m much more interested in their impact on brain dysfunctions and overall disability—which matter the most to patients and their caretakers—than in their effects on biomarkers, which may or may not be able to reliably predict the most meaningful clinical outcomes.

I’m also eager to learn why the lower dose worked even better than the higher ones. Solving that puzzle could teach us important lessons about tau biology and about how to dose these types of therapies in the future.

Now that we have anti-amyloid therapies on the market and tau-targeting therapies proving their worth in phase 2 clinical trials, what does the future of Alzheimer’s treatment look like to you?

I’m incredibly optimistic. We’re about to enter an era of combination therapy. Alzheimer's is a complex, multi-faceted disease. Just as we treat cancer and prevent heart attacks and strokes with a cocktail of drugs that tackle the underlying processes from different angles, the future of Alzheimer’s medicine will likely involve targeting multiple causal drivers simultaneously.

Imagine a future where a patient is given an anti-amyloid drug to clear out plaques, a tau-lowering agent to protect their neurons from dysfunction and degeneration, and perhaps additional therapies to reduce neuroinflammation and block the detrimental effects of APOE4.

By combining these evidence-based strategies, we should move closer than ever to transforming Alzheimer's from a devastating diagnosis with an inevitably poor outcome into a manageable and, hopefully, even preventable condition.