The amyotrophic lateral sclerosis exposome: recent advances and future directions

Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration with typical survival of only 2-5 years from diagnosis. The causes of ALS are multifactorial: known genetic mutations account for only around 70% of cases of familial ALS and 15% of sporadic cases, and heritability estimates range from 8% to 61%, indicating additional causes beyond genetics. Consequently, interest has grown in environmental contributions to ALS risk and progression. The gene-time-environment hypothesis posits that ALS onset occurs through an interaction of genes with environmental exposures during ageing. An alternative hypothesis, the multistep model of ALS, suggests that several hits, at least some of which could be environmental, are required to trigger disease onset, even in the presence of highly penetrant ALS-associated mutations. Studies have sought to characterize the ALS exposome - the lifetime accumulation of environmental exposures that increase disease risk and affect progression. Identifying the full scope of environmental toxicants that enhance ALS risk raises the prospect of preventing disease by eliminating or mitigating exposures. In this Review, we summarize the evidence for an ALS exposome, discussing the strengths and limitations of epidemiological studies that have identified contributions from various sources. We also consider potential mechanisms of exposure-mediated toxicity and suggest future directions for ALS exposome research. The amyotrophic lateral sclerosis exposome is the lifetime accumulation of environmental exposures that increase disease risk and affect progression. This Review summarizes the literature that has sought to characterize aspects of the amyotrophic lateral sclerosis exposome and considers potential mechanisms of exposure-induced toxicity. Amyotrophic lateral sclerosis (ALS) is a fatal disease of motor neuron degeneration, with both genetic and environmental factors contributing to the risk and rate of disease progression.The gene-time-environment hypothesis of ALS posits that disease arises from an interaction of genetic burden with environmental burden over the life course.The multistep model of ALS posits that multiple 'hits', some of which are presumed to be environmental in origin, trigger disease onset, even in carriers of highly penetrant mutations.Epidemiological studies suggest potential contributions to the ALS exposome from pesticides, occupational exposures, sports and physical activity, metals, air pollution, trauma, electromagnetic fields, the gut microbiome, diet and lifestyle factors.The mechanisms underlying the effects of environmental factors on ALS risk remain incompletely understood but might involve neurotoxicity from specific environmental toxins, microbiome-mediated changes, epigenetic restructuring, systemic and central inflammation and excitotoxicity.Most studies of the ALS exposome have a retrospective design using questionnaires and are, therefore, prone to recall bias and other limitations. Future studies will require prospective, longitudinal designs that include quantification of exposures in biosamples in addition to questionnaires.