Models of ALS aetiology. The multistep hypothesis of ALS is a model that conceptualises the pathological development of ALS as a sequence of steps (Xx-Xxxxxxx et al., 2014). Consistent with this hypothesis, if the log incidence of ALS is plotted against the log age of onset the resulting slope is linear, and the regression coefficient can be used to quantify the number of steps needed for disease development, with the number of steps being regression coefficient (b)+1. Analysis of data from Australian, Japanese and South Korean registers have replicated the initial finding from multiple European registers that on average, people with ALS will take 5-6 steps to reach ALS (Xxxxx et al., 2020; Xxxxx et al., 2019). Analysis of incidence in people with ALS that have variants in ALS causing genes show that in people with SOD1 variants on average 2 steps are needed to develop disease, C9orf72 it is 3 steps and TARDBP it is 4 steps (Chiò et al., 2018). A study comparing risk of prior diagnosis of schizophrenia and prior diagnosis of cardiovascular disease found that after controlling for prior death as a competing risk, people with prior cardiovascular disease have 3 steps needed to develop ALS (Xxxxxx, Trabjerg, Xxxx, & Agerbo, 2020). Men also have on average, half a step less than women to develop ALS. Each step is not thought to be exposure to an individual risk factor, but likely represents a biological process, possibly happening at a cellular level. Population-level data is required to test whether incidence as a function of age is mathematically consistent with a multistep process. To find subgroups with different numbers of steps required for disease onset, detailed genotype and phenotype information needs to be available on all people within a population. People develop ALS after encountering fewer additional exposures, such as those with SOD1-mediated ALS may provide subgroups with a smaller exposome to investigate potential environmental triggers of ALS. Establishing a population register in for ALS in the UK will lay the foundation for data collection needed for ALS subgroup analysis. The multistep model is also consistent with the liability-threshold model of disease risk (Xx-Xxxxxxx and Xxxxxxxx, 2013). Liability is defined as the burden of exposures, which may be a mixture of genetic or environmental factors, and everyone will have a different liability, assumed to be normally distributed, and if an individual’s liability is above the disease threshold then disease develops...
