Vigorous Physical Activity Accelerates ALS Symptom Onset in Sporadic and Genetic Cases
Maurizio Grassano1, Federico Tosetto1, Cristina Moglia1, Andrea Calvo1, Adriano Chio1
1ALS Center, Department of Neuroscience, University of Turin
Objective:
To determine whether physical activity causally affects age at onset in Amyotrophic Lateral Sclerosis (ALS), including among pathogenic variant carriers, and to assess whether genetic predisposition to vigorous activity acts through independent pathways.
Background:
Physical activity has long been suspected to be an ALS risk modifier, with observational studies linking higher activity to younger age at onset. However, confounding by generational exercise patterns has limited causal inference. Recent Mendelian randomization studies suggest vigorous activity causally influences ALS risk, but how this affect individuals with pathogenic ALS variants remains less known, with direct implications for genetic counseling.
Design/Methods:
We conducted two complementary analyses. First, in 250 incident ALS cases from PARALS with validated lifetime activity histories, we modeled age at onset adjusting for birth cohort and diagnostic period. Second, in 1,043 ALS cases, we tested whether a polygenic score (PGS) for vigorous activity associated with age at onset independently of measured activity, using interaction and mediation analyses. We stratified by pathogenic variant carrier status to assess counseling relevance.
Results:
Higher lifetime sport activity associated with 5.1 years earlier onset (p = 2.0 × 10⁻⁶) after temporal adjustments. Critically, this effect persisted in 31 pathogenic variant carriers (−4.7 years; p = 0.048). The vigorous activity PGS independently predicted younger onset (r = −0.084; p = 0.006; direct effect −1.36 years, p = 0.026), with no interaction with measured activity (p = 0.35) or mediation (p = 0.75), suggesting distinct biological pathways.
Conclusions:
Strenuous physical activity causally accelerates ALS onset through mechanisms at least partly independent of genetic liability for exercise behavior. The persistence of this effect in pathogenic variant carriers indicates that physical activity could influence symptom onset even in genetically determined disease, warranting discussion in pre-symptomatic genetic counseling.
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