In 2020, 5.8 million Americans were suffering from Alzheimer’s. According to the CDC, that number is expected to balloon to 14 million by 2060. A cure for those people has long remained elusive, but that might change sooner than we think thanks to a new study illustrating how Alzheimer’s-associated proteins accumulate in the brain. The findings, published Friday in Science Advances, arm researchers with novel insights into how the disease progresses and could lead to new ideas for more effective treatments.
Alzheimer’s is a disease defined by misbehaving proteins, according to Tuomas Knowles, a researcher at the University of Cambridge and a co-senior author of the new study. One of these proteins is called tau. In Alzheimer’s disease, tau starts to misbehave, forming clumps inside brain cells, interfering with their ability to communicate with one another.
Reducing the accumulation of these tau clumps might be one way to fight Alzheimer’s disease, but first, scientists have to figure out how the accumulation is happening.
Knowles told The Daily Beast there are two main processes at work in tau’s takeover of the brain. One process involves tau clumps spreading from one part of the brain to another. The other process involves tau replication—the clumps growing and multiplying in place.
A disease can only move as fast as its slowest step allows (also called the “rate-limiting” step), so Alzheimer’s researchers are deeply interested in figuring out which of these processes that govern tau's progression through the brain is slower. “If you want to intervene therapeutically, you have much more effect if you pick the rate-limiting step,” said Knowles. “If you pick a step which is not rate limiting, you run the risk of actually not having any kind of benefit.”
A lot of research has focused on how to stop the tau clumps from spreading, but according to the new study, this might not be an effective way to treat the disease. Using five different sets of data on the brains of people with Alzheimer’s, the researchers found that by the middle and later stages of the disease, tau replication was actually a much more important factor than tau spreading.
Brian Kraemer, a professor at the University of Washington who was not involved in the study, told The Daily Beast that the approach used in this study, “is a new idea for the field. I think it could tell us some important things that we don’t really understand very well about how tauopathies [neurodegenerative diseases involving tau] progress. I thought it was pretty cool.”
For the first time, the researchers were also able to determine an average for how fast this replication is happening in humans. Using data from post-mortem brain tissue as well as brain scans from living Alzheimer’s patients, the researchers found that the average replication time is about five years. This rate is orders of magnitude slower than the rate observed in experiments in test tubes and mice. In a field that has often struggled with translating research from animals to humans—dozens of drugs have reversed Alzheimer’s symptoms in mice while none have been able to accomplish this in humans—this finding underscored the importance of studying disease processes in actual patients.
The slow tau replication rate in humans is also good news on its own. “What it tells us is, the environment in the brain has evolved to almost completely keep this process under control,” said Knowles.
“I like to be optimistic about these things,” he said. “You don't actually need to do that much to this number before you've actually cured the disease. [The doubling time] doesn't have to go to a million years… You just have to slow it down maybe by a factor of two to three. And then it's just slow enough such that it’s not a problem during our lifetime.”
The next step for researchers will be to find drug candidates, molecules that can modulate this rate of replication and potentially slow the disease down to a point where a patient’s cognitive function is hardly impaired.
Kraemer added that the methods used in this study could also provide interesting insights into other debilitating neurodegenerative diseases that also involve abnormal tau proteins. This includes argyrophilic grain disease (a relatively common form of dementia); and chronic traumatic encephalopathy (CTE), which is seen in football players and others who have suffered repeated head injuries.
Knowles looks forward to future research using molecular-level tools to answer larger-scale questions about neurodegenerative diseases. “We're really keen to bring our insights and tools as chemists, where we can actually deal with molecular-level phenomena,” he said. “But now actually being able to do this in the real person, with real patient data. I think it’s incredibly exciting.”