Amyotrophic Lateral Sclerosis as a Multistep Process in the United States: A Population‐Based Study

ABSTRACT Background Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease that typically results in death within 3–5 years from symptom onset. However, little is known about the environmental exposures, clinical aspects, or social determinants of health factors that may be associated with the disease. Multistep modeling has been previously applied to cancer research, demonstrating a linear relationship between logs of incidence and age. This method may help to understand the mechanisms involved in the development of ALS in the United States (e.g., environmental exposures, genetic mutations). We aim to assess whether ALS is a multistep process among patients enrolled in the largest ALS registry in the world—the United States' National ALS Registry. Methods Incident ALS cases, defined as confirmed and likely, cases between 2012 and 2019 were obtained from the National ALS Registry. Age‐standardized incidence was calculated for all cases and by sex. The log incidence of ALS was regressed against the log of age (years) at case determination, on average, for each year and by sex. Findings Between 2012 and 2019, there was a mean of 5253 incident ALS cases (confirmed or likely) per year. We identified a linear relationship between the log of the average incidence and log age overall ( r 2 = 0.99), for men ( r 2 = 0.99), and for women ( r 2 = 0.98). The incidence slope estimates were 4.8 (95% CI: 4.4–5.1) overall, 4.7 (95% CI: 4.4–5.1) for men, and 5.0 (95% CI: 4.5–5.5) for women. Interpretation The linear relationships observed overall, for men, and for women are consistent with a multi‐step process. The slope estimates, on average, are approximately 5.0, which suggests that the development of ALS is a six‐step process. Further investigation of these steps can elucidate potential risk factors and treatments for ALS.