Identification of the development process behind ALS could lead to new therapies
Background
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.
Methods
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.
Findings
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 r2=0·95, Ireland r2=0·99, Italy r2=0·95, the Netherlands r2=0·99, and Scotlandr2=0·97; overall r2=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).
Interpretation
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.
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