The association between ALS and reduced cardiovascular disease is hypothesis-generating, driving novel pathway discovery, and not necessarily secondary to premorbid physical activity.

Those living with the adult neurodegenerative syndrome of amyotrophic lateral sclerosis (ALS) naturally want to understand why. A monogenetic association may be identified in approximately 10% of cases. For the majority, ALS has a polygenetic and environmental ‘multiple hit’ model of pathogenesis, like many cancers, and supported indirectly through analysis of the incidence of ALS in relation to age.1 Neurologists who regularly diagnose those with ALS observe a characteristic syndrome of progressive weakness with strikingly focal symptom onset, but recognise an increasingly complicated phenotypic taxonomy and molecular heterogeneity.2 The causes of ALS may be diverse, and none are yet certain at a cellular level. There is also likely to be a significant pre-symptomatic period.3

A frequent perception concerning the premorbid lifestyle of those with ALS involves athleticism, typified by the eponymous ‘Iron Horse’ Lou Gehrig.4 Premorbid physical activity has been shown to be increased in those who develop ALS, in multiple studies spanning more than a decade, although with important exceptions (reviewed in Gallo et al).5 A reduced incidence of premorbid cardiovascular disease has been separately noted.6 7 Visser et al now probe the ‘fitness hypothesis’ further. Specifically, they explore the cause of death in the parents of those with ALS.8

Their headline result is that death from cardiovascular disease is significantly lower in the parents of the sporadic ALS group compared with the control parent group, although with no difference in the overall survival and no influence of parental gender apparent. This analysis was adjusted for potential confounds, including for some previously identified ALS premorbid associations, including diabetes9 and lower body mass index,6 though not smoking. In a non-adjusted analysis, the parents of the much smaller subgroup with familial ALS (n=86, defined as having first-degree, second-degree or third-degree relative with ALS or known C9orf72 expansion) were more likely to die from causes listed as neurodegenerative (approximately two thirds of whom were labelled as dementia, with one third as Parkinson’s disease). The reduced incidence of premorbid cardiovascular disease in ALS patients might be assumed to be a corollary of physical activity. However, no firm conclusions can be drawn from this study’s finding of a lack of association between the ALS patient levels of physical activity in leisure time and the rates of cardiovascular disease or survival of their parents, given that parental levels of activity were not captured.

The axiom that association is not causation cannot be overstated. Being fit does not necessarily drive someone to develop ALS, although cellular stress and injury response pathways appear superficially appealing and have biological plausibility.10 There is no basis to suggest that clinicians should advise asymptomatic carriers of ALS-causing genes to limit their physical activities, or deviate from standard medical practice in promoting measures to reduce cardiovascular risk. Rather, Visser et al’s study reinforces the broader hypothesis of a shared genetic profile between cardiovascular fitness and ALS. The authors proffer altered premorbid metabolism as a source for potential common pathways. Equally one might envisage a structural and functional configuration of the human motor system more conducive to physical activity, with an associated reduced cardiovascular risk for many, but inadvertently placing pressure on more fragile cellular protein homeostastic pathways for the few who develop ALS Alternatively, a ‘high performance’ motor system might be a more permissive neuronal architecture for disease propagation, appearing over-represented among those with ALS but from an entirely independent molecular chain of events.

Can anyone develop ALS? If not, what is the basis for any resistance? These are fundamental questions to pursue. Studying premorbid disease associations represents an important way to generate novel hypotheses, as well as to test existing concepts and potentially shared molecular pathways, with the aim of finding the most effective targets for therapeutic intervention.