Stefano Borgonovo, Gianluca Signorini, and Pietro Anastasi are just three of more than 30 professional footballers who have died from amyotrophic lateral sclerosis (ALS), a degenerative motor neuron disease that appears to disproportionately affect soccer players. The condition has even been dubbed “the footballers’ disease” or “the dark disease of football” by journalists. The reason for this apparent link, however, remains unclear.

A group of Italian researchers has proposed a new hypothesis in Medical Hypotheses — a forum for ideas in medicine and related biomedical sciences. It will publish interesting and important theoretical papers that foster the diversity and debate upon which the scientific process thrives. The researchers suggest that a previously overlooked factor may be involved: the roar of stadium crowds.

ALS, while among the more common neurodegenerative diseases after Parkinson’s and Alzheimer’s diseases, is still relatively rare, with an incidence of 2.1-3.8 cases per 100,000 people per year in Europe. However, the risk is two to six times higher among Italian and American professional football players than among the general population, and onset occurs much earlier. Several explanations have been proposed, including repeated head trauma, doping, and exposure to pesticides used on playing fields. Yet none fully accounts for the disease’s unique epidemiology in athletes.

Physical activity itself does not appear to increase ALS risk, nor is incidence higher in sports where doping is equally or more prevalent, such as cycling. Other proposed factors — head injuries, pesticides, or a genetic link between ALS risk and a predisposition for competitive sports — also fail to explain the pattern: Elevated ALS incidence is largely observed in elite leagues. In Italy, for example, players in Serie A, the top-tier league, face nearly double the risk than those in Serie B, the second division.

From Observation to Study

“In 2013, our group, together with US epidemiologists, published research on light pollution and its potential implications for Parkinson’s disease. That led me to consider whether prolonged exposure to other environmental stimuli, such as repeated noise over the years, could also harm the brain. Several years earlier, the first study had reported higher ALS incidence among Italian footballers; for me, the connection was immediate,” said lead author Roberto Maggio, professor at the Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy, in an interview with Univadis Italy.

Unlike amateur players, professionals in top leagues are exposed to substantial ambient noise. Anyone who has attended a Serie A match knows that Italian stadiums can reach 95-110 dB, with peaks of 123-140 dB — comparable to a rock concert or a jet engine at takeoff. Top-league players are thus regularly subjected to high-intensity sound, whereas lower-league or amateur players rarely encounter such noise levels.

Limits Remain

It is important to emphasize that this remains a preliminary working hypothesis that has not yet been supported by clinical or epidemiologic data. “The manuscript submitted to Medical Hypotheses was reviewed by seven experts: one completely negative, two neutral, three positive, and one extremely positive. From the comments, it appears that the less favorable reviewers were clinicians, less inclined to accept extrapolations or hypotheses lacking epidemiological evidence, while the more favorable reviewers were likely basic researchers, more open to new ideas. In short, until supporting clinical and epidemiological data are available, some skepticism is natural, particularly among clinicians,” Maggio told Univadis Italy.

In their article, the researchers outline a detailed clinical study protocol that could either support or refute their hypothesis. The proposed study would monitor at least 500 athletes and compare them with at least 250 non-athletes for noise exposure during matches, blood-brain barrier (BBB) permeability, and markers of neurodegenerative disease. “Given our expertise and resources, our group cannot directly conduct a clinical-epidemiological study of this scale,” Maggio noted, expressing hope that other research groups might take up the challenge. If confirmed — or refuted — the findings could not only improve athlete health but also advance understanding of ALS etiology and molecular mechanisms, benefiting both athletes and the general population.

Role of the BBB

High-intensity acoustic exposure occurs in many occupational settings, but professional footballers experience it simultaneously with extremely intense — and often anaerobic — physical activity. According to Maggio and colleagues, the BBB may link these factors. It is known that exposure to sufficiently loud sounds can increase BBB permeability; ultrasound has even been experimentally used to facilitate drug delivery to the brain. For audible sounds in humans, data are still limited, though some animal studies support the concept.

As the authors noted, repeated exposure to loud noise “combined with high-intensity physical activity and systemic inflammation from repeated, intense sessions, may create a physiological state conducive to neurotoxic insult once the BBB is compromised. The intense physical demand during matches induces high circulating levels of metabolic byproducts (lactate and ammonia) and proinflammatory cytokines such as TNF-α [TNF-alpha], IL-1β [interleukin 1-beta], and especially IL-6, each of which can become neurotoxic if allowed entry into the central nervous system.” Other potentially neurotoxic substances — such as organophosphates and herbicides used on playing fields — may also more easily penetrate the BBB once it has been weakened by sound exposure.

Football and Music

This hypothesis may help explain why ALS risk appears concentrated in sports, countries, and leagues that draw large crowds — and thus generate high noise levels. According to the authors, sports such as basketball or ice hockey do not show the same increased risk. These activities are largely aerobic, producing less lactate accumulation, and players are exposed to lower sound intensity. Similarly, goalkeepers — whose physical demands differ markedly from those of outfield players — do not share the significantly higher ALS risk observed in their teammates.

Another group potentially affected under this model is musicians — particularly in pop and rock genres, where high sound levels often coincide with intense physical exertion. “In the final paragraph of our paper, we highlight an interesting observation from one reviewer, noting anecdotal evidence suggesting numerous ALS cases among musicians and singers,” said Maggio. For singers, he added, “high-intensity sound exposure comes from the body itself: The vocal cords, located just below the brain, generate vibrations that may affect brain structures.”

However, the authors emphasized that rigorous studies and statistical confirmation of causality are still lacking.

This story was translated from Univadis Italy.