Commentary: Mapping the Human Exposome: Without It, How Can We Find Environmental Risk Factors for ALS?

Amyotrophic lateral sclerosis (aLS) is a devastating neurodegenerative disease. It has been in the public awareness recently because of the Ice Bucket Challenge phenomenon and the multiaward-winning film, The Theory of Everything, which tells the story of the renowned physicist Stephen Hawking, focusing on the time around his diagnosis. aLS kills 1 in every 300 people and does so over a period of a few months to a few years through a slow paralysis that eventually affects the diaphragmatic muscles and therefore prevents breathing. although it was first described nearly 150 years ago, the causes remain largely unknown. the heritability of aLS is about 60%, which implies that 40% of the phenotypic variance is explained by environmental factors, although this does not mean that environmental factors contribute to only 40% of cases, as many cases may occur due to a combination of genetic and environmental factors. While great progress is being made in identifying the genetic component of risk, the environmental aspect has been far more challenging, in part because the lack of an apparent disease mechanism makes it difficult to determine which environmental exposures to focus on. Furthermore, although the most promising ideas about the possible causes of other diseases such as cancer and asthma have often come from population comparisons, there is limited valid global data on aLS incidence or prevalence outside european populations. a number of possible occupational or environmental causes have been suggested, but there is little definitive evidence to date. In this edition of EpidEmiology, 2 papers try to address this issue by examining the evidence for risk factors that have been previously reported for aLS: military service and exposure to electric shock or electromagnetic fields. military service is an attractive subject for epidemiologic studies of aLS. the study cohort is relatively clearly defined and documented, and the potential risk factors include several candidates for aLS, including athleticism, high exercise or fitness levels, exposure to toxins or vaccines, and traumatic injury. Sport and fitness have been considered important in aLS because the motor system is key to sporting success, and the motor pathways are the primary system affected in aLS. Furthermore, it is a frequent anecdotal report of neurologists specializing in aLS that their patients are very fit. a typical presenting complaint is, “I was at the gym when I realized I could no longer do X.” High levels of sporting activity also sit well with the excitotoxic hypothesis of aLS in which overstimulation of motor nerves by glutamate during extreme