Evidence of stage-specific cognitive reserve effects on longitudinal cognition in amyotrophic lateral sclerosis

About 50% of amyotrophic lateral sclerosis (ALS) patients develop cognitive-behavioural impairment, yet longitudinal studies diverge on onset and extent of decline. Cognitive reserve (CR) may modulate cognitive trajectories, although longitudinal evidence remains limited. We aim to characterize cognitive trajectories in ALS and healthy aging and to examine the role of CR proxies in shaping cognitive change over time. About 268 participants (169 patients, 99 controls) were evaluated twice over 6 to 18 months using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Mixed models were used to predict initial ECAS performance (ECAS1), and cognitive slope (ECAS2-ECAS1) using CR proxies (education, work and leisure), ECAS21-ECAS12 interval, demographics (age, sex, psychiatric medication) and clinical factors (disease duration, onset-region, respiratory capacity, functional decline, C9orf72 mutation and behavioural symptoms). In patients, education (p < .001) and leisure (p < .001) positively predicted ECAS1. However, longitudinally, education and leisure had negative main effects on cognition, protecting against decline through interactions with clinical variables. In controls, more education and leisure predicted better cognition through main effects and interactions. CR appears to exhibit a dynamic, phase-dependent influence in patients and controls, supporting initial cognitive performance and potentially offering subtle protection as disease progresses. The observed non-linear effects of all CR proxies and subgroup-specific effects highlight the importance of considering clinical context, time and initial cognition when evaluating CR's role in ALS.