The role of physical exercise in the development of Amyotrophic lateral sclerosis for people with certain other risk factors

Summary by Selina Natalie Beal, PhD student, the University of Sheffield
November 2021

Original article

Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes. DOI:

26 May 2021

Lay summary


Amyotrophic lateral sclerosis (ALS) is caused by a complex combination of both genetic risk factors and environmental modifiers. Having a genetic risk factor (or mutation) does not mean that an individual will develop ALS, and this variation is called penetrance. Improving our understanding of environmental modifiers and how they impact genetic risk factors is important to understanding this variable disease penetrance. One potential environmental modifier that has been proposed but with conflicting reports is exercise.

This was first identified from observations that professional sportspeople develop ALS more frequently than the wider population, alongside having a younger age of onset (the age at which ALS symptoms begin to present). Attempting to identify environmental risk factors is challenging because of how variable exposures to environmental factors are, and the number of genetic risk factors associated with ALS – it is likely that specific environmental exposures are only relevant for people with specific genetic risk factors.

This study aimed to investigate the link between frequent and strenuous leisure-time exercise, described as 15- 30 minutes 2/3 days a week, and ALS.

Why is the study important?

This study is important as it confirms the association between ALS and frequent strenuous exercise.

What did the authors do and how did they do it?

Firstly, genome-wide association study (GWAS) data was analysed using a technique called Mendelian Randomisation. This technique uses genetics as a ‘tag’ to measure lifetime exercise exposure. Secondly, a case-study of ALS patients and healthy controls was used to identify how strenuous activity affected gene expression in ALS patients. Gene expression is the process by which information from the gene is used to make proteins. To follow on from this, a study was undertaken of ALS patients with the C9ORF72 genetic mutation to identify whether exercise could explain the variation in disease penetrance in individuals with C9ORF72-ALS.

What are the results?

Using this ‘tag’ this study showed that those individuals who undergo frequent and strenuous exercise are at a higher risk of developing ALS. Moreover, there was a dose-response effect such that more exercise led to higher risk of ALS. It is important to note that this result is valid for a population but does not tell us much about what happens to individuals. It is not possible to identify which individuals have developed exercise-induced ALS and which individuals have developed ALS independent of any exercise they did or did not do. This is important because we know that exercise is beneficial for a wide range of physical and mental health conditions. In addition, sedentary behaviour was not shown to be protective against ALS. Within the case study, 52% of known ALS-related genes had altered expression after strenuous exercise, confirming this association. This suggests that there is an interaction between known genetic causes of ALS and physical exercise. The final study showed that for patients with C9ORF72-ALS, the more historical physical activity they had undertaken, the younger their age of onset of ALS. It should be noted that this final part of the study contained less than 20 C9ORF72-ALS patients and therefore was underpowered relative to the other results. Future studies will look to confirm this result in larger numbers of patients.

The authors hypothesised that exercise is likely to cause motor neuron injury in people with specific genetic risk factors. They suggest that ALS patients with the C9ORF72 expansion have a predisposition to exercise-induced motor neuron injury. Further research is required to fully understand the mechanism of exercise-related ALS.

What do the finding mean going forward for people with the disease?

Future research studies will develop this finding to make precise risk predictions based on genetics: for example, an individual may have their genome sequenced and used to assess their risk of ALS if they exercise once a day or once a week etc. This would allow people, particularly family members of ALS patients, to make informed decisions about their exercise choices. It is hoped that establishing a comprehensive understanding of the relationship between different genetic risk factors and the environmental modifiers that influence them, will lead towards treatments that can be tailored to each individual patient, known as “personalised medicine”.

Author list

Thomas H Julian, Nicholas Glascow, A Dylan Fisher Barry, Tobias Moll, Calum Harvey, Yann C Klimentidis, Michelle Newell, Sai Zhang, Michael P Snyder, Johnathan Cooper-Knock, Pamela J Shaw

Publication details including date of publication:

2021 Jun;68:103397. doi: 10.1016/j.ebiom.2021.103397. Epub 2021 May 26.

PDF of lay summary

The role of physical exercise in the development of ALS for people with certain other risk factors (PDF, 129KB)