To describe in depth the cognitive-behavioral characteristics of a cohort of ALS patients carrying SOD1 pathogenetic variant.

All patients with ALS seen at the Turin ALS expert center in the 2009–2021 period undergoing both cognitive/behavioral and extensive genetic testing were eligible for the study. Only patients with SOD1 pathogenetic variants (n=28) (SOD1-ALS) and those without variants of 46 ALS-related genes (WT-ALS) (n=829) were enrolled in the study. Patients and controls underwent a neuropsychological battery encompassing executive function, verbal memory, language, visual memory, visuoconstructive abilities, attention/working memory, psychomotor speed, non-verbal intelligence, cognitive flexibility, social cognition, and behavior. Tests scores were compared with Mann-Whitney U test on age-, sex-, and education-corrected scores. Cognition was classified as normal (ALS-CN); isolated cognitive impairment (ALSci); isolated behavioral impairment (ALSbi); cognitive and behavioral impairment (ALScbi); frontotemporal dementia (ALS-FTD).

Among the SOD1-ALS patients, 17 (60.7%) were classified as ALS-CN, 5 (17.9%) ALSci, 5 (17.9%) ALSbi and one (3.6%) ALScbi. No patient had ALS-FTD. SOD1-ALS performed worse than controls in all explored domains. Compared to WT-ALS, SOD1-ALS patients had a worse performance in the  Story-based Empathy Task emotional attribution score (p=0.021) and the ECAS Verbal Fluency subscore (p=0.015). At cognitive domains level, Social Cognition (p=0.002) and Language (p=0.037) were significantly more impaired in SOD1-ALS than in WT-ALS.

Cognitive impairment is much more common in SOD1 patients than was previously believed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. Our findings may have relevant implication both in the clinical and in the research setting, also at the light of the recently approved treatment for SOD1-ALS.