Listening for Whispers: How a Tiny Protein Could Transform HD Research

A new study bolsters our confidence that neurofilament light (NfL), a protein released by damaged brain cells, could serve as an early warning signal for Huntington’s disease (HD) progression—appearing in the blood many years before symptoms start. Tracking NfL levels may revolutionize HD research by helping predict when symptoms will appear, improving clinical trial design, and opening the door to earlier interventions.

Cracking the Silent Phase

One of the trickiest things about HD is its long silent phase—those years or even decades when someone carries the HD gene but hasn’t yet developed any symptoms. Most people with the gene for HD don’t start noticing changes until their 30s or 40s, but behind the scenes, the disease has been quietly reshaping the brain for years.

Scientists believe that starting treatments early—long before symptoms appear—will have the best shot at slowing or even stopping HD in its tracks. But how can we intervene early if we don’t know exactly when someone will develop symptoms?

What if there was a way to detect the earliest whispers of HD before the disease starts making itself known? That’s been one of the biggest goals in HD research for a long time, and a growing body of evidence suggests that the tiny protein NfL is giving us hope that it might be possible.

What is NfL?

NfL isn’t a new protein on the block, it’s been hanging out in our brains all along. Brain cells release little bits of NfL when they’re damaged or under stress. Think of NfL like a distress signal—a subtle siren going off in the brain, hinting that something isn’t quite right. The more damage happening, the louder that siren gets.

Scientists can measure NfL in the blood with a simple blood test, making it an easy and non-invasive way to peek inside the brain. In fact, clinical trials testing new HD medicines are already using NfL to help measure how well those treatments are working. But what if NfL could tell us even more, like who’s likely to develop symptoms soon, or how quickly HD is progressing? That’s exactly what a new study set out to investigate.

The Gift That Keeps on Giving

“Imagine standing outside and hearing a faint siren in the distance. The closer it gets, the louder and faster it sounds. That’s what NfL seems to be doing in HD—giving us an early warning of what’s coming and how quickly it’s approaching.”

This study followed people with HD for an impressive 14 years—long enough to span everything from the rise of Instagram to the return of high-waisted jeans. Back in 2009, a group of volunteers with and without the HD gene signed up for the Cambridge Huntington’s Sleep Study. While the original goal was to track sleep patterns, participants also gave blood samples and completed tests to measure their thinking and movement abilities.

Fast forward to today, and those carefully stored blood samples have become a scientific goldmine. The researchers recently asked participants for permission to test their old blood samples for NfL levels, and 21 gene-positive and 14 gene-negative folks agreed. This kind of long-term follow-up study is incredibly valuable to research, and it shows how one study can keep giving back to the HD community, even years later.

Warning Signs in the Blood

At the start of the study, everyone with the HD gene was still symptom-free. But as the years went on, some people with the HD gene began showing those subtle early signs of HD—small changes in movement or thinking abilities that doctors can measure on a standardized rating scale.

When the researchers looked at the NfL levels in everyone’s blood, they found something remarkable. People who eventually developed symptoms had higher levels of NfL in their blood—even as early as 10 years before any symptoms appeared. This is consistent with a recent study that also found increases in NfL long before symptoms were predicted to appear.

Even more interesting, the speed at which NfL levels rose over time seemed to match how severe symptoms became. It wasn’t just about having more NfL, it was about how fast those levels were climbing.

Imagine standing outside and hearing a faint siren in the distance. The closer it gets, the louder and faster it sounds. That’s what NfL seems to be doing in HD—giving us an early warning of what’s coming and how quickly it’s approaching.

A Window into the Future

If scientists can confirm these findings in larger studies, it could be a game-changer for people with HD. Imagine having a simple blood test that could give you a sense of whether symptoms might start in the next decade, and how quickly the disease might progress. That kind of knowledge could be incredibly empowering.

For some, having that information might help with making decisions about family planning, careers, or finances. Others might prefer to live life as they always have, without that extra layer of information. Both choices are equally valid. What matters is giving people the option to know if they want to.

Supercharging Clinical Trials

NfL could also help solve one of the biggest challenges in HD clinical trials—how much people’s progression rates vary from person to person. Right now, everyone in a trial is compared to the average rate of disease progression, but not everyone follows the average timeline. If someone is naturally a fast progressor, a drug might look like it’s not working even if it’s actually slowing things down.

“With NfL, researchers could tailor trials more precisely, identifying the people who are likely to show symptoms sooner and tracking whether the drug is slowing down their NfL rise. This could make trials faster, smaller, and more reliable, helping new treatments reach families sooner.”

With NfL, researchers could tailor trials more precisely, identifying the people who are likely to show symptoms sooner and tracking whether the drug is slowing down their NfL rise. This could make trials faster, smaller, and more reliable, helping new treatments reach families sooner.

What’s Next?

Like any good detective story, there are still a few missing clues. Because this study used stored samples from a different research project, not all participants had blood samples at every time point—life happens! The researchers were upfront about these study limitations, and noted that the next step will be to confirm these findings in bigger studies with more consistent data collection.

Still, this study is an exciting first step toward making NfL a powerful tool for tracking HD progression, testing new treatments, and—maybe one day—giving people with the HD gene a clearer view of what the future might hold. The whispers of HD may be faint, but thanks to NfL, we’re starting to hear them a little more clearly.

Learn more

• Original research article, "A 14-year longitudinal study of neurofilament light chain dynamics in premanifest and transitional Huntington’s disease". (open access)