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

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.