Cognitive and Behavioural Profile of SOD1-ALS Across the ALS-FTD Spectrum: A Systematic Review

Abstract

Amyotrophic Lateral Sclerosis (ALS) is increasingly recognized as a multisystem disorder. However, SOD1-associated ALS has traditionally been regarded as an exclusively motor phenotype. This systematic review challenges that paradigm by characterizing the cognitive and behavioural profiles of SOD1 mutation-related ALS. Following PRISMA guidelines, a systematic PubMed search identified 17 eligible studies. Across the included studies, encompassing 222 patients with SOD1 variants, three of the analyzed subjects fulfilled the diagnostic criteria for frontotemporal dementia (FTD), and a larger proportion exhibited multidomain cognitive deficits, including executive dysfunction, language impairment, and working memory decline. Behavioural disturbances, such as apathy, emotional lability, and mental rigidity, were also prominent. The historical assumption that SOD1 mutations completely spare cognitive networks likely reflects an under-recognition of subtle manifestations, compounded by the limited sensitivity of earlier screening tools. These findings indicate that cognitive and behavioural involvement can occur in SOD1-ALS, highlighting a highly heterogeneous phenotype. Encompassing varying degrees of severity—from subtle differences in neuropsychological test scores to formal FTD diagnoses—the current evidence points towards possible variant-specific phenotypes rather than a uniform cognitive syndrome. Routine multidomain cognitive screening is crucial in this population. Properly characterizing these non-motor features allows for more accurate disease staging, better monitoring of clinical progression, and the implementation of truly personalized care strategies.