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

Summary

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 Scotland r²=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.

Funding

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).

Introduction

Amyotrophic lateral sclerosis is a neurodegenerative disease that mainly affects upper and lower motor neurons. It shows complex inheritance: about 5% of people with amyotrophic lateral sclerosis have a family history of the disease or frontotemporal dementia in a first degree relative and up to 20% have an affected relative in more extensive population-based family studies.¹

Amyotrophic lateral sclerosis has several intriguing features (many shared with other neurodegenerative diseases) that remain unexplained. First, amyotrophic lateral sclerosis is an adult-onset disorder, even in individuals born with a gene mutation that increases the risk of the disease. Although such a mutation is carried from birth, many people remain healthy into old age and do not develop the disease.² Others remain completely healthy until disease onset seems to begin suddenly (typically between the age of 50 and 70 years), and progresses rapidly.³ It is unknown why a pathological genetic change present from birth is expressed only in adult life, in some people but not others, even for high-penetrance mutations (eg, in the SOD1 gene), and why, when the mutation is expressed, the pathological process progresses rapidly. Furthermore, several amyotrophic lateral sclerosis genes show pleiotropy, in which the same gene mutation can result in different phenotypes. For example, individuals with expansion of a hexanucleotide repeat in the C9orf72 gene can remain healthy, or might develop amyotrophic lateral sclerosis, frontotemporal dementia, or amyotrophic lateral sclerosis–frontotemporal dementia. The same mutation might also predispose to schizophrenia, depression, and Parkinson's disease¹ but in every case the burden seems to be specific to a particular subgroup of cells. Additionally, amyotrophic lateral sclerosis seems to start in one neural region and spread,⁴ but no genetic or environmental factor has yet been found to decide the site of onset.

Several of these characteristics are shared with cancer, which suggests that, despite the differences between cancer and neurodegeneration (eg, cancer is an uncontrolled proliferation of cells, whereas neurodegeneration is the result of the death of cells),⁵ other shared features remain to be discovered.

Since the 1950s, multistep models have been applied to the study of population patterns of cancer and, although the level of mathematical support remains a matter of debate, they have yielded insights into the likely causes of cancer and in some cases the identification of the steps involved.6, 7, 8, 9, 10 These models generally show that a plot of epithelial cancer incidence against age has an exponential pattern; incidence is proportional to age raised to the power six. This association is consistent with the hypothesis that these cancers are the end result of seven successive mutations.8, 9, 10, 11 Different patterns are reported with some specific cancers—eg, breast cancer, in which cell replication at particular stages of life might have an important role.

Like cancer, amyotrophic lateral sclerosis might be a multistep process in which several sequential steps are needed. For example, a high-penetrance disease-causing mutation would still need the accumulation of the remaining steps to result in disease, which would take time. This scenario would explain both the adult onset and the finding that not every individual carrying a mutation develops disease.

Multistep models have not been used previously in the study of neurodegenerative disease. Therefore, we used a model originally applied to cancer epidemiology to test the hypothesis that amyotrophic lateral sclerosis is a multistep process.