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  • Review Article
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The amyotrophic lateral sclerosis exposome: recent advances and future directions

Nature Reviews Neurology volume 19, pages 617–634 (2023)Cite this article

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Abstract

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.

Key points

  • 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.

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Fig. 1: Studying the amyotrophic lateral sclerosis exposome.
Fig. 2: Gene–environment interactions in amyotrophic lateral sclerosis.
Fig. 3: Potential exposome-mediated pathophysiological mechanisms of amyotrophic lateral sclerosis.
Fig. 4: Study design for future amyotrophic lateral sclerosis exposome studies.

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Acknowledgements

The authors are grateful to the patients attending the Pranger ALS Clinic at the University of Michigan, along with their families, whose interest in clinical research and participation in studies have made advances in amyotrophic lateral sclerosis (ALS) exposome science possible. The authors also acknowledge the faculty and staff at the ALS Center of Excellence for their help in performing these studies and thank E.J. Koubek for help with the supplementary information. S.A.G. and E.L.F. acknowledge funding from the National ALS Registry/CDC/ATSDR (1R01TS000289, R01TS000327); National ALS Registry/CDC/ATSDR CDCP-DHHS-US (CDC/ATSDR 200-2013-56856); the ALS Association (20-IIA-532); NIEHS (K23ES027221, R01ES030049), NINDS (R01NS127188, R01NS120926); the NeuroNetwork for Emerging Therapies; the NeuroNetwork Therapeutic Discovery Fund; the Peter R. Clark Fund for Amyotrophic Lateral Sclerosis Research; the Sinai Medical Staff Foundation; Scott L. Pranger and the University of Michigan.

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  1. These authors contributed equally: Stephen A. Goutman, Masha G. Savelieff.

Authors and Affiliations

  1. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Stephen A. Goutman, Dae-Gyu Jang & Eva L. Feldman

  2. NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, USA

    Stephen A. Goutman, Dae-Gyu Jang & Eva L. Feldman

  3. Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, USA

    Masha G. Savelieff & Junguk Hur

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Contributions

S.A.G., M.G.S., J.H. and E.L.F. contributed substantially to discussion of the article content. All authors wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Eva L. Feldman.

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Competing interests

S.A.G., D.-G.J. and E.L.F. are employees of the University of Michigan. M.G.S. and J.H. are employees of the University of North Dakota. S.A.G. and E.L.F. are listed as inventors on a patent, issue number US10660895, held by the University of Michigan, entitled ‘Methods for treating amyotrophic lateral sclerosis’ that targets immune pathways for use in amyotrophic lateral sclerosis (ALS) therapeutics. S.A.G. has served on a Data and Safety Monitoring Board and as a medical adviser for an ALS documentary. E.L.F. has consulted for Biogen.

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Nature Reviews Neurology thanks J. Mandrioli, S. Vucic and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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We searched PubMed for articles in the English language, using with the following terms in addition to ‘amyotrophic lateral sclerosis’: ‘agriculture risk’, ‘air pollution’, ‘clinical trial diet’, ‘detoxifying gene’, ‘detoxifying SNP’, ‘diet risk’, ‘education polygenic’, ‘electromagnetic’, ‘environment’, ‘exposure’, ‘faecal microbiota transplant’, ‘FMT’, ‘gene environment’, ‘gene exposome’, ‘geographic distribution’, ‘head trauma’, ‘immunity environment’, ‘immunity exposome’, and ‘immunity exposure’, ‘infectious agent’, ‘ketogenic diet’, ‘mechanism’, ‘metals’, ‘metals blood’, ‘metals plasma’, ‘microbiome’, ‘microbiome risk’, ‘military’, ‘mutation environment’, ‘mutation exposome’, ‘neuroinflammation environment’, ‘neuroinflammation exposome’, ‘neuroinflammation exposure’, ‘occupational exposure’, ‘persistent organic pollutant’, ‘persistent organic pollutant blood’, ‘persistent organic pollutant plasma’, ‘pesticide’, ‘pesticide blood’, ‘pesticide plasma’, ‘pollutant’, ‘probiotic’, ‘professional sports’, ‘polygenic environment’, ‘polygenic exposome’, ‘socioeconomic’, ‘spatial clustering’, ‘traffic’, ‘trauma’. The search focused on articles published from 1st January 2017 to 23rd November 2022; however, older seminal papers were also considered. In addition, articles from the authors’ personal reference lists were included. Articles were selected on the basis of relevance to this Review.

Supplementary information

Glossary

Dual hit models

Models incorporating both genetic mutations and environmental exposures.

Epigenetic age

A composite measure of DNA methylation across specific CpG sites that is associated with chronological age.

Familial ALS

Heritable amyotrophic lateral sclerosis occurring in individuals with a family history of the illness.

Heritability

The extent to which a trait can be explained by inheritance.

Mendelian randomization

A method that examines causality of a modifiable exposure on a disease by using measured variation in genes with characterized functions.

Microbiome

A community of microorganisms that dwells within a specific habitat. In the context of the human microbiome, the habitat compromises organs, for example, the gut microbiome or the skin microbiome.

Microbiota

All of the living microorganisms within a microbiome.

Monogenic

A mode of inheritance in which a trait is attributable to a single gene.

Penetrant

Penetrance is defined as the extent to which a genetic trait manifests in an individual. Mutations that are highly penetrant are more likely to manifest phenotypically than are those with low penetrance.

Polygenic

A mode of inheritance in which a trait is attributable to several genes.

Sporadic ALS

Amyotrophic lateral sclerosis occurring in individuals without a family history of the illness.

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Goutman, S.A., Savelieff, M.G., Jang, DG. et al. The amyotrophic lateral sclerosis exposome: recent advances and future directions. Nat Rev Neurol 19, 617–634 (2023). https://doi.org/10.1038/s41582-023-00867-2

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