For most of the past few decades, scientists chasing treatments for Alzheimer’s disease have focused on attacking the buildup of one protein in the brain that contributes to the disease: amyloid. They’ve had some success; there are currently two anti-amyloid treatments approved
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
That’s why scientists at the Alzheimer’s Association International Conference in London are reporting a series of encouraging results in testing for and reducing levels of tau, creating new ways to potentially manage the disease
A tau-lowering approach
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
Researchers used a type of gene-based approach that blocks cells from making tau. It works by attaching to the genetic instructions cells use to produce tau, which prevents the production of the protein
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.
“This is the first trial to ever show reduction in tau,” says Dr. Lawren VandeVrede, assistant professor of neurology at the UCSF Memory and Aging Center and a principal investigator in the study. “Other trials have shown reduction in the rate of accumulation of tau, but not in the actual reduction of tau in the brain. And importantly, we saw clinical benefit of doing that.”
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.”
Mucke disagrees with others in the field who maintain that some amount of tau is important for maintaining the normal structure of neurons; based on his work with animals, he believes that if disease processes like those involved in Alzheimer’s disease start to appear, then tau becomes an enabler to the disease, essentially fueling the abnormal mechanisms along. “There are probably quite a few functions that tau is involved in that, under normal circumstances, don’t do anything bad,” he says. “But if a disease comes along—not only Alzheimer’s, but epilepsy and autism spectrum disorders—tau reduction can dampen the down processes that lead to these diseases.”
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 study is still an early trial of the experimental drug. But if diranersen’s effects are confirmed by more studies, which Biogen says it plans to conduct, then VandeVrede can imagine a future where the drug might one day be taken alongside an anti-amyloid drug. (The ones currently on the market can at best slow cognitive decline by about 30%.) “If we see the benefit of tau, then my instinct is that clinicians will think, ‘What if we use both?’” says VandeVrede. “If you slow down something with a drug, and can then slow it down again with another drug, you end up with something that may look like stabilization. And that would be a huge win in the Alzheimer’s world.”
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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
In a new study published in JAMA, researchers at Mass General Brigham and Harvard Medical School found that levels of a form of tau found in the blood, called ptau217, can identify people at higher risk of rapid cognitive decline. In a group of more than 2,700 cognitively normal people who were followed for years, those with the highest ptau217 levels had a 78% higher likelihood of becoming cognitively impaired in 10 years, and a 38% likelihood in five years, compared to those with lower levels. The researchers found that ptau217 levels in the blood provided more predictive information about cognitive decline beyond brain scans and genetic testing, the approaches most often used today.
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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
“I think this will change accessibility in early detection of Alzheimer’s disease dramatically,” says Rachel Buckley, associate professor of neurology at Mass General Brigham, who led the study. ”Especially if there is something we can do about treatment in the future for people who don’t yet have symptoms.”
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.”
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That may still be a few years away. At the moment, people with higher tau levels still don’t have a specific treatment that will help them lower their levels—although studies have hinted that some basic prevention strategies, like maintaining a healthy heart, getting enough sleep, remaining socially engaged, and staying physically active, can slow or reduce the risk of Alzheimer’s. More rigorous studies of these behavioral interventions will produce results in coming years, Sperling says
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.
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But even with such tests and potential treatments in the future, questions about access remain. Screening for people without symptoms of Alzheimer’s is not currently covered by major payers and Medicare. Two years ago, the U.S. Preventive Services Task Force (USPSTF), a federally convened panel of independent experts that reviews available evidence on disease prevention and rates the strength of the data, determined that there was not enough evidence to support the benefit of screening the general population for Alzheimer’s disease. But things are evolving fast, says Maria Carrillo, chief science officer of the Alzheimer’s Association, and the group is laying the groundwork to encourage payers, including Medicare, to cover the cost of screening for tau should additional studies continue to support its importance in identifying those at higher risk.
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.”
