Lou Gehrig was a star baseball player who led the New York Yankees to six World Series titles before he was diagnosed with a devastating disease in 1939, when he was still in his mid-30s. The disease, amyotrophic lateral sclerosis (ALS), causes the motor neurons that enable muscle movement to deteriorate, gradually leading to the loss of the ability to move, eat, speak and even breathe. Gehrig’s illness, which had already been documented for decades, helped raise public awareness before the first baseman passed away in 1941—so much so that “Lou Gehrig’s disease” later became a common name for the condition.

There is a long list of professional athletes who, like Gehrig, died from ALS. Among professional soccer players in Italy, for example, there have been reports of a higher than average number of ALS cases. Researchers have also found similarly elevated rates among athletes in the U.S. National Football League. These observations have led many scientists to wonder whether doing elite sports—or, more broadly, engaging in intense exercise—might increase the risk of developing the neurodegenerative disease.

Despite the many studies that have examined whether physical activity is tied to ALS, researchers have yet to pinpoint a clear answer. Some investigations have revealed a link, while others have not. These conflicting findings have led some researchers to examine whether other, related factors, such as metabolism or genetic predisposition, might provide alternative or complementary explanations. “Once you take this evidence all together, it looks like there is something else underlying this association rather than physical activity alone,” says Valentina Gallo, a neuroepidemiologist at the University of Groningen in the Netherlands.

Too Much Movement?

The idea that physical activity might be involved in ALS goes back decades. During a 1962 conference, British neurologist MacDonald Critchley pointed to Gehrig’s case and noted that the fact that he was a professional athlete might not be a coincidence. “Nothing has been said about the possible role in ætiology of a previous habit of athleticism,” Critchley said at the time. “I have the uncomfortable feeling that a past history of unnecessary muscular movement carried out for no very obvious reason may be followed in later life by the development of motor neurone disease in a statistically significant number of cases.”

In the years that followed, many investigators set out to assess whether this hunch was correct. Some studies—such as those of Italian soccer players or American football players—suggested that there was, indeed, something about high levels of exercise that increased the risk of the illness. Researchers also reported that certain jobs that required strenuous physical labor, such as metalworking or farming, could increase the likelihood of a diagnosis. Other studies, however, failed to find a heightened risk of ALS in individuals who had some of those occupations—or among people who, in general, had a very active lifestyle. “Physical activity is a very tricky exposure to evaluate in terms of types, intensity and duration” says Elisa Longinetti, a postdoctoral researcher at the Karolinska Institute in Sweden. “That’s why I think we’ve found so many conflicting results in several studies investigating its effect on ALS.”

One of the challenges in doing this research is determining how best to measure the level of physical activity a person was exposed to throughout their life. In a study published on October 20 in Neurology, Angela Rosenbohm, a neurologist at Ulm University in Germany, and her colleagues tried to get a better estimate of people’s lifetime physical activity by asking them very specific questions about the types of activities they engaged in during work and leisure and how those activities changed across different life stages.

The team recruited people from a large database that comprised all newly diagnosed ALS cases in Swabia, a southwestern region of Germany. For each patient, the researchers also enrolled two healthy subjects who were randomly selected from the general population. They ended up with 393 participants with ALS and 791 healthy recruits. Participants were asked to report how much physical activity they had engaged in at age 20, 30, 40, 50 and 60—as well as the type, duration and intensity of the activities they were involved in (for example, whether a given activity was a work-related and if it made them break out into a sweat).

This study revealed that physical activity and ALS may be connected in a more complex way than previously considered. The researchers found that only those who had high levels of physical activity from their occupation—but not from leisure activities—had an increased risk of ALS. Rosenbohm says that rather than being a consequence of physical activity, this link may arise from other underlying factors, such as higher levels of toxins or pollutants in workplaces where the most physically demanding jobs take place—which would be consistent with what has been reported in other studies. She adds that professional athletes (who were not explicitly examined in this study) may be exposed to pesticides on the field.

Rosenbohm’s team found that while there was no correlation between general exercise levels and risk of ALS, there was an association between the former and outcomes of the disease. People who were very active or sedentary were more likely to die from ALS earlier than their moderately active counterparts. It also suggests that moderate exercise might benefit people with the disease—both after diagnosis and before their symptoms appear.

The researchers also discovered that, around five to 10 years before they were diagnosed, many patients with ALS reported a steep drop in their physical activity, which was much more pronounced than that seen in healthy individuals—suggesting that the disease may cause changes in the body that start many years before the deterioration of motor neurons begins.

But Rosenbohm’s study, like many others that have come before it, has one major limitation: it relies on participants’ self-reports. Gallo explains that it is difficult for people who have a disease in which movement is impaired, such as ALS, to remember past physical activity in an unbiased way. The only method to truly remove this bias, Gallo adds, is to document physical activity levels in a so-called prospective cohort study, which observes a large group of people over time. In any such group that is followed for long enough, some individuals are expected to be diagnosed with ALS. But these resource- and time-intensive studies are few and far between.

In 2016 Gallo and her colleagues conducted such a study of ALS using data on 472,100 people from 10 different European countries that had been collected between 1992 and 2002 for a long-term investigation on cancer and nutrition. All the subjects filled out a questionnaire about their physical activity, both during work and leisure time. Information on deaths and causes of death were also available. By the time this study took place, 219 of these individuals had died from ALS. The team found that, contrary to the many retrospective studies on the topic, being active appeared to very slightly decrease—rather than increase—the risk of dying from the disease.

Alternative Explanations

Studies suggest that there may also be other explanations for the link between intense physical activity and ALS.

One idea is that exercise alone might not heighten the risk for ALS in the general population but could be harmful for people who are genetically predisposed to the disease. In a study published in EBioMedicine this spring, researchers reported that higher levels of past physical activity were associated with earlier disease onset only in patients with a mutation in the C9ORF72 gene—the most common cause of inherited ALS. Additionally, they found that exercise altered the amount of protein produced by the C9ORF72 gene. The authors of the paper say that their findings may explain the inconclusive effects of exercise reported in prior studies, most of which did not examine the role of genes.

Another hypothesis is that it is not the exercise itself but rather a person’s metabolism that is the real culprit. Researchers have found, for example, that people with a higher body mass index are less likely to develop ALS and that losing weight after developing the disease leads to more rapid progression.

“It seems that the people who develop ALS have a sort of accelerated metabolism,” says Alberto Ascherio, a neuroepidemiologist at Harvard University. Ascherio and his colleagues have found signs of abnormal metabolism in blood samples collected from people years before they were diagnosed with ALS. This suggests that something is happening in patients long before their symptoms appear—which is consistent with the reduction in physical activity that Rosenbohm’s team observed in its latest study, Ascherio adds. “What that is, we are still unable to pin down,” he says.

The question of whether altered metabolism is a cause or an effect of the disease remains unanswered, however. “There is a huge wealth of evidence showing that patients with ALS have increased metabolism,” Gallo says. But in most cases, “these are people with the disease already, so you don’t know if this led to the development of the disease or if it was actually a consequence of the disease.”

The bottom line, according to Ascherio, is that the connection between intense physical activity and increased risk of ALS is too uncertain to make specific recommendations about whether people should be more or less active to stave off the disease. ALS is a relatively rare condition—so even if working out less would be protective, it is important to remember that exercise can help prevent other, more common illnesses, such as cardiovascular disease, stroke and dementia, Ascherio adds. “Keep enjoying your physical activity,” he says.