Even as incidence and prevalence for Amyotrophic lateral sclerosis (ALS) are increasing in the United States, the motor neuron disease will continue to be considered an orphan disease for many generations.  People 65 years and older residing in the United States can expect to live another 10-20 years on average, but an ALS diagnosis currently cuts short the period of time remaining for 50% of patients to 5 years or less.  We conducted a systematic literature review using PRISMA methodology to survey hypothesis-driven, cohort, case-controlled, population-based studies that explored the role of environmental factors.  A low article-to-review ratio of approximately 4 articles for every review paper suggests a need to evaluate how the field assesses environmental factors for association or causal relationships to ALS.  We applied the Bradford Hill criteria to reclassify environmental factors for causality or association with current findings in the literature. Results ranked the cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA), formaldehyde, selenium, and heavy metals, specifically mercury, manganese, and zinc and copper among the most likely to be causal.  Significant gaps in research for even the highest-ranked environmental factors include a lack of metabolic pathway specificity and human cohort studies.  A further survey into model research and studies with a geospatial focus indicates gaps in our ability to align etiology pathways with epidemiology between animals and humans, as well as across geographic regions.  Reported incidence rates predict a high number of cases in at-risk groups (ages 65-80) relative to population size in Scotland (incidence rate in units of cases per 100,000 people per year of 3.9 per 100,000 person-years predicts 282 incidences), France (incidence rate of 3.2 per 100,000 person-years predicts 304 incidences), and Japan (incidence rate of 0.69 per 100,000 person-years predicts 165 incidences) if extended across the country.  Meanwhile, very little is known of incidence rates outside of Europe and the Western Pacific.  If future research begins to focus resources toward the highly ranked environmental toxins, energy may be subsequently spent associating these triggers to changes in the genome or epigenome.

Amyotrophic lateral sclerosis (ALS): What do we really know about the role of the environment?

ACS Fall 2021

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