Identifying Modifiable Factors and Their Joint Effect on Amyotrophic Lateral Sclerosis: A Prospective Cohort Study in the UK Biobank.

BACKGROUND

Hypothesis-driven studies have linked numerous risk factors to amyotrophic lateral sclerosis (ALS). However, the full extent of their diversity and co-occurrence has not been adequately appreciated. This study aims to comprehensively explore the modifiable risk factors for ALS and to evaluate the potential benefit of controlling these factors.

METHODS

This prospective cohort study utilized data from UK Biobank participants enrolled between 2006 and 2010 for whom complete data were available. An exposome-wide association study (EWAS) was employed to screen for modifiable risk factors, adjusted for sex and age. The main outcome was the first recorded diagnosis of ALS. The associations of modifiable risk factors with ALS risk were assessed using hazard ratios and 95% confidence intervals. The population attributable fraction (PAF) was used to estimate the joint effects of modifiable factors.

RESULTS

This study included a total of 326,050 participants and assessed 184 modifiable risk factors. During follow-up, 744 participants were diagnosed with ALS for the first time. EWAS, adjusted for sex and age, identified 45 modifiable factors associated with ALS incidence across six domains (excluding early life), including varicella, lower education, and peak expiratory flow. Analysis using the PAF indicated that 25.94%-87.40% of ALS cases could potentially be prevented.

CONCLUSIONS

In this study, newly identified risk factors for ALS through the EWAS may serve as targets for future studies. Interventions targeting modifiable risk factors, particularly those related to lifestyle and socioeconomic status, may help reduce the incidence of ALS.