A recent study published in the Lancet by a group of researchers at the University of Sheffield has identified a potential cause behind some cases of ALS. Looking at data from a variety of ALS datasets, as well a large-scale biomedical database in the United Kingdom called the UK Biobank, the researchers claim to have found a causal relationship between frequent, intense physical exercise and some cases of ALS.

Many in the ALS community have been understandably concerned about these findings. However, Dr. Johnathan Cooper-Knock, an author on the paper and a geneticist and neurologist at the University of Sheffield, cautions that these results do not provide evidence that anyone should stop exercising at this point.

Dr. Cooper-Knock joined us to explain more about the study, and what else scientists need to understand to making recommendations about exercise based on these findings.

ALS TDI: What would you say is the main question you were attempting to answer with this paper?

Johnathan: I think that the high-level question is: “is there a causal link, not just an association, between exercise and ALS?” We know that in people with ALS the most vulnerable motor neurons are those that supply fast twitch muscle fibers involved in vigorous anaerobic activity. So, we tried to focus on exercise that was associated with activation of those muscle fibers. What we found is that exercise increases your risk of ALS.

But the thing I want to emphasize early is that we only showed a population level effect. So, at the population level, more exercise means more risk of ALS. What we can't do at the moment is make individual level predictions. What we think is that only certain individuals are vulnerable to exercise induced ALS, and until we know how to identify those individuals, we're not advising anybody to change their habits. Exercise is very beneficial. And even further, we don't yet know how to test whether a particular patient has exercise induced ALS.

ALS TDI: How did you conduct this study? What were the methods?

Johnathan: We used a technique called Mendelian randomization, or MR. One of the problems with ALS research is you're often dealing with quite small sample sizes. It's hard to get a group of ALS patients where you’ve also measured exercise. But what Mendelian Randomization allows you to do is to measure exercise in a different population, so we use the UK Biobank, and then take that measure and apply it in a genetic study of ALS that includes thousands and thousands of patients. Because you can do that kind of trick of movement across two different datasets, then you can use tens of thousands of patients in your study. That's quite hard to do with an observational study.

In addition to the Mendelian randomization, we also looked at exercise in general. We looked at gene expression changes in non-ALS patients when they exercise. That gave us a group of genes that are changed in response to exercise. We found those genes are enriched with genetic risk factors for ALS. Our idea there is that whenever you exercise, you activate a set of genes. But if your genetic background is such that some of those genes are broken, then every time you activate that gene, it causes toxicity. So, the more you exercise, the more you activate the toxicity, and the higher your risk for ALS.

And then the third part of what we did is we looked at the specific genetic subtype of ALS associated with mutations in C9orf72. Now, I just want to make a caveat that this was the smallest part of our study. We had about 17 patients. But what we showed that in that in a small subset, higher levels of physical activity were associated with earlier age of onset. But I think that's something where you'll need replication. Whereas I think some of the other stuff, like the Mendelian Randomization study, is very powerful and stands on its own.

ALS TDI: Can you tell me a little bit like what would qualify as frequent, intense exercise?

Johnathan: What we used were measures from the UK Biobank, so we were looking at leisure time physical activity, described as strenuous, twice or more per week every week, according to a survey. The definition within the UK Biobank survey is “strenuous,” but it’s left open within the questionnaire. I can't give you a precise definition because the participants didn't have one.

But I think what we're looking for is anaerobic exercise. We made no differentiation between, say, jogging versus rugby, which would have higher incidence of head injury. So, our measure is almost certainly not capturing head injury, because head injury can be very inconsistent across the different exercises we measured.

ALS TDI: Obviously, there's more research that's needed down the line. But at this point, who would you say should be concerned about these findings?

Johnathan: The key thing is we want to not do harm, and exercise is clearly beneficial, and not exercising is clearly harmful. Until we can make a recommendation to allow somebody to make a risk decision for themselves, to say “if your genetic background is this, exercising will affect your risk for developing ALS this much,” then we're not telling anybody to change their activity. I think it's really important to emphasize that. Our focus going forward is now identifying specific individuals with specific genetic backgrounds and trying to make predictions about the risk of ALS.

ALS TDI: And just to be abundantly clear about this, this study concerns how exercise before someone is diagnosed with ALS affects their risk for getting it later, right? It doesn't have anything to do with exercise for people who already have been diagnosed with ALS?

Johnathan: I'm glad you brought that up. It's a really important point. We're talking about historical exercise over a lifetime affecting the risk of developing ALS. For people who have ALS, that’s a totally different question. And in that case, there's a lot to do with the specific patient and their own specific symptoms.

To learn more about this paper, as well as the benefits of exercise for people who have been diagnosed with ALS, be sure to attend our upcoming ALS TDI Town Hall on Exercise and ALS, featuring Dr. John Cooper-Knock, at 4pm ET, July 28th, 2021. You can find more information and sign up here.

For more information about the ALS Therapy Development Institute’s research to end ALS, click here.