But while amyloid plaques are important in Alzheimer’s disease, memory and cognitive symptoms frequently only start once another protein, tau, also starts accumulating in the brain. While some experts believe the brain needs some amount of tau in order to function normally and maintain the architecture of neurons, abnormal tau tangles can contribute to cognitive problems associated with Alzheimer's.
Developing anti-tau medications is a challenge, because tau starts to function abnormally inside of cells—unlike amyloid, which aggregates into plaques outside of cells, which makes the amyloid clumps easier to target with things like antibodies. In the first study of its kind, researchers at the biotechnology company Biogen reported early results from their study of diranersen, a drug that shuts down tau production at the source.
The study included 416 people with Alzheimer’s disease who were randomly assigned to receive one of three different doses of diranersen or a placebo twice a year, delivered directly into the cerebrospinal fluid via a lumbar puncture. After 18 months, those who received diranersen had 50%-65% less tau in their brains, as detected by PET scans, compared to those who got a placebo treatment. This reduction seemed to translate into cognitive benefits: people who took the drug slowed their cognitive decline by up to 50% on certain brain tests that measure memory, recall, reasoning skills, and orientation. Interestingly, the trial showed that the participants treated with the highest dose of diranersen did not show greater improvement than those treated with the lowest dose; all derived some benefit.
Dr. Lennart Mucke, director of the Gladstone Institute of Neurological Disease and professor of neurology and neuroscience at the University of California San Francisco, published the groundbreaking paper involving mice that first showed the potential of reducing tau to address the progression of Alzheimer's disease. "It's very gratifying for me, of course," he says of the results. "Quite a few of my colleagues were concerned whether overall tau reduction would be well tolerated, and I always thought that it was by far the most pragmatic approach. Certainly our animal studies always suggested that even partial reduction is beneficial. And this Biogen trial clearly shows that also seems to be the case in humans."
Debate on this point can, and should, continue, says Mucke. But the important lesson of the study, he adds, is that reducing tau matters, regardless of how it might be involved in the process of Alzheimer's disease.
The tau trackers
If there are clinical benefits to reducing tau, then doctors will need a good way to measure tau and track it in the brain. Other researchers at the conference reported success with a blood test that can detect tau levels up to 10 years before Alzheimer’s symptoms appear.
Blood tests that measure tau are currently reserved for people who already have symptoms: either to help confirm Alzheimer’s disease or to rule it out. But these results are the first to show that a blood-based tau test could be useful in cognitively normal people—to identify those at highest risk of going on to develop Alzheimer’s before they get sick.
The findings open a path to screening for and identifying people in the general population who might be at high risk of developing Alzheimer’s, similar to the way other conditions are managed to prevent disease rather than waiting until symptoms appear. These results "are a game-changer, in the same way we think about screening for cancer where people get tested before any symptoms," says Dr. Reisa Sperling, senior author of the paper, a professor of neurology at Harvard, and director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital. "For 10 years, I’ve been saying the same should be true of Alzheimer’s, and it’s finally [starting to] come true.”
A multi-pronged approach to prevention
Researchers from Lund University also reported results of a study comparing how accurately primary care physicians and dementia specialists diagnosed Alzheimer’s in their patients if they used the experimental blood test for tau as well as other currently available tools, such as brain scans, family history of the disease, and a blood test on the market that compares amyloid to tau levels. They found that both groups of doctors were about 90% accurate when including the test, and that the blood test was especially useful for primary care doctors in ruling out Alzheimer’s.
What’s clear is that after decades of frustratingly slow progress, Alzheimer’s disease research is finally gaining momentum, and the latest findings point to the importance of looking beyond amyloid to including tau-based strategies as well. “We’re beginning to prepare for what that future is going to look like," says Carrillo, "and it’s exciting."
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