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Lancet Neurol. 2014 Nov;13(11):1108-1113. doi: 10.1016/S1474-4422(14)70219-4. Epub 2014 Oct 7.

Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study.

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King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK. Electronic address:
ALS Center, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy; Neuroscience Institute of Turin (NIT), Turin, Italy.
Euan MacDonald Centre for MND Research, University of Edinburgh, Edinburgh, UK.
Motor Nerve Clinic, King's College Hospital, London, UK.
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK; National Hospital for Neurology and Neurosurgery, London, UK.
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands.
King's College London, Institute of Psychiatry, Department of Clinical Neuroscience, London, UK.
Department of Neurology, Brighton and Sussex Medical School Trafford Centre for Biomedical Research, University of Sussex, Falmer, East Sussex, UK.
Department of Neurology, 'Amedeo Avogadro' University of Eastern Piedmont and Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy.
Salvatore Maugeri Foundation, IRCSS; Scientific Institute of Milan, Milan, Italy.
Department of Neurology, Addenbrooke's Hospital, Cambridge, UK.
Faculty of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, UK; Centre for Public Health Research, Massey University Wellington Campus, Wellington, New Zealand.



Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process.


We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register.


We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0·95, Ireland r(2)=0·99, Italy r(2)=0·95, the Netherlands r(2)=0·99, and Scotland r(2)=0·97; overall r(2)=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5-5·0), with similar estimates for men (4·6, 4·3-4·9) and women (5·0, 4·5-5·5).


A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues.


UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).

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