Objective:

To investigate whether cognitive function in ALS patients differs between sexes.

Background:

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder exhibiting sexual dimorphism in its epidemiology and clinical presentation. While females typically experience a later onset and a higher incidence of bulbar symptoms, sex differences in cognitive manifestations remain underexplored.

Design/Methods:

We evaluated 450 individuals with ALS (225 females) for cognitive function, with females and males matched using propensity score matching at a 1:1 ratio for age, site of disease onset, time since disease onset, ALSFRS-R score, and education level. We compared cognitive performances between males and females using an extensive neuropsychological battery. Analyses were performed on cognitively normal subjects and the subgroup of ALS patients with cognitive impairment.

Results:

Among ALS patients without overt cognitive impairment, males performed worse than females on verbal memory measures (RAVL-IR -0.76, 95% CI -1.18 to -0.34, P=0.0005; RAVL-DR -1.02, 95% CI -1.46 to -0.58, P<0.0001). Conversely, females exhibited greater deficits in visual memory and visuoconstructive abilities (ROCF-DR -0.37, 95% CI -0.70 to -0.04, P=0.0293; ROCF-IR -0.77, 95% CI -1.47 to -0.07, P=0.0390). These differences persisted in ALS patients with cognitive impairment. Additionally, females with ALS showed a slight, non-significant increase in disinhibition compared to males.

Conclusions:

Our findings indicate that cognitive performance in ALS differs between sexes, even when demographic and disease severity variables are matched. Specifically, males with ALS exhibit greater preservation of visuoconstructive abilities, while females show better preservation of verbal memory. These patterns are evident in both cognitively normal and cognitively impaired patients, suggesting that sex-related differences in cognitive impairment may emerge early and persist throughout the disease course. Our data might confirm a role for cognitive reserve mechanisms in ALS.