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The epidemiology of ALS: a conspiracy of genes, environment and time

Abstract

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease of motor neurons, resulting in worsening weakness of voluntary muscles until death from respiratory failure occurs after about 3 years. Although great advances have been made in our understanding of the genetic causes of ALS, the contribution of environmental factors has been more difficult to assess. Large-scale studies of the clinical patterns of ALS, individual histories preceding the onset of ALS, and the rates of ALS in different populations and groups have led to improved patient care, but have not yet revealed a replicable, definitive environmental risk factor. In this Review, we outline what is currently known of the environmental and genetic epidemiology of ALS, describe the current state of the art with respect to the different types of ALS, and explore whether ALS should be considered a single disease or a syndrome. We examine the relationship between genetic and environmental risk factors, and propose a disease model in which ALS is considered to be the result of environmental risks and time acting on a pre-existing genetic load, followed by an automatic, self-perpetuating decline to death.

Key Points

  • Amyotrophic lateral sclerosis (ALS) is a syndrome rather than a single disease; understanding which clinical patterns go together is a challenge but will improve our ability to identify the causes

  • The frequency of ALS seems to be constant in European-derived populations worldwide

  • For other populations—where sufficient data are available—the risk appears to be lower than in European-derived populations

  • Environmental risk factors are difficult to study because the search space is infinite

  • No replicable, definitive environmental risk factors for ALS have yet been identified

  • The data are consistent with a model in which a pre-existing genetic load is acted on by time and environmental exposures until a tipping point is reached and neurodegeneration begins

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Figure 1: Pathological, phenotypic and genetic groupings of amyotrophic lateral sclerosis.
Figure 2: The liability threshold model of disease.
Figure 3: The gene–time–environment model of ALS.
Figure 4: Relationship between genetics, environment and time under different scenarios.

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Acknowledgements

We thank the Motor Neuron Disease Association of Great Britain and Northern Ireland, the ALS Association of America, the Irish Health Research Board, Research Motor Neuron, The Irish Motor Neuron Disease Association, The Irish Institute of Clinical Neuroscience, the Angel Fund, and the ALS Therapy Alliance for support. A. Al-Chalabi receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The work leading up to this publication was funded by the European Community's Health Seventh Framework Programme (FP7/2007–2013; grant agreement number 259867).

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A. Al-Chalabi has consulted for Cytokinetics and Biogen Idec and receives royalties for the books The Brain (Oneworld Publications) and Genetics of Complex Human Diseases (Cold Spring Harbor Laboratory Press). O. Hardiman has consulted for Cytokinetics, Biogen Idec and Novartis.

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Al-Chalabi, A., Hardiman, O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 9, 617–628 (2013). https://doi.org/10.1038/nrneurol.2013.203

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