Toward a Behavioral Reserve Model in Amyotrophic Lateral Sclerosis.

Abstract

Behavioral impairment is common in amyotrophic lateral sclerosis (ALS) and strongly affects autonomy, caregiver burden, and outcomes, yet predictors of vulnerability remain unclear. We investigated whether premorbid regulatory traits and socio-educational exposures are associated with behavioral phenotypes in ALS within a behavioral reserve framework. We analyzed 965 consecutively assessed patients with ALS from a prospective tertiary-center cohort. Behavioral impairment was measured using the Frontal Systems Behavior Scale (FrSBe; family-rated before and after onset) and, in a subset (n = 633), the Edinburgh Cognitive and Behavioural ALS Screen-Carer Interview (ECAS-CI). Theory-driven hierarchical logistic regression models tested associations between behavioral outcomes and premorbid behavioral regulation, education, occupation, and a Social Interaction Index, including interaction effects. Prespecified sensitivity analyses addressed potential bias in premorbid estimates. Premorbid behavioral regulation showed the strongest associations with behavioral impairment across all FrSBe models. Higher combined educational attainment and social exposure were associated with lower odds of impairment, with a significant interaction across multiple behavioral domains. These patterns persisted in restricted sensitivity analyses. Reserve proxies were not significantly associated with ECAS-CI total impairment, although domain-specific effects were observed. These findings provide empirical support for a behavioral reserve framework in ALS, in which premorbid regulatory traits and socio-educational exposures are associated with behavioral vulnerability. Although causal inference is limited, reserve-related factors may contribute to non-motor heterogeneity in ALS and may inform future approaches to early behavioral risk stratification. ANN NEUROL 2026.