From Snow to Hill to ALS: An epidemiological odyssey in search of ALS causation

J Neurol Sci. 2018 Aug 15:391:134-140. doi: 10.1016/j.jns.2018.05.016. Epub 2018 May 21.


Background: Establishing mechanisms of disease causation in neurodegenerative diseases has long seemed to be beyond the pale of traditional epidemiological tools. Establishing a plausible mechanism for initiation of amyotrophic lateral sclerosis (ALS) has appeared a particularly elusive goal. This review shows that a likely mechanism for ALS initiation may be inferred by applying classical methods of epidemiological inference.

Key points: Advances in characterizing the biology of ALS suggest that most cases of ALS are cortically-generated, part of the ALS-FTD spectrum, with focal onset and spread by contiguity within the motor super-network. Evidence-based methods identified the most credible exogenous risk factor - smoking. AB Hill's nine viewpoints to inferring causation from association were invoked. The most likely mechanism consistent with smoking being a risk factor for ALS was inferred: cumulative DNA damage, akin to cumulative somatic mutations in carcinogenesis. Focal onset supports the concept that these changes, occurring in a single cell, may trigger the cascade leading to clinical ALS. The plausibility of this mechanism was affirmed by its coherence/consistency with other observations in sporadic, familial and western Pacific ALS.

Conclusion: Application of traditional epidemiological reasoning suggests that cumulative DNA damage may contribute to disease onset in ALS.

Keywords: ALS causation; DNA damage; Evidence-based methods; Genotoxicity; Smoking.

Publication types

  • Review

MeSH terms

  • Amyotrophic Lateral Sclerosis / epidemiology*
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / physiopathology
  • DNA Damage
  • Epidemiologic Research Design
  • Humans
  • Smoking / epidemiology