Abstract Amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) is a fatal neurodegenerative condition, and identifying its modifiable risk factors is a critical public health issue. This large-scale prospective cohort study investigated the role of sleep-related factors in ALS-FTSD risk using data from 396,918 UK Biobank participants. Eight sleep-related exposures were assessed, and Cox proportional hazards regression was employed to evaluate their associations with ALS-FTSD incidence. Subgroup and sensitivity analyses were conducted to validate the robustness of our findings. At baseline, participants had a mean age of 56.31 ± 8.12 years, with 47.5% being male. In the fully adjusted Cox model, organic sleep disorders (G47) (HR: 1.81, 95% CI: 1.21, 2.72, P = 0.004), hypersomnia (G47.1) (HR: 36.53, 95% CI: 9.04, 147.55, P