Cognitive reserve as a modulator of cognitive decline and of behavioral symptoms in patients with amyotrophic lateral sclerosis

<i>Introduction</i>: Amyotrophic lateral sclerosis (ALS) has heterogeneous manifestations ranging from motor neuron degeneration to cognitive and behavioral impairment. This study aims to clarify the interactions between cognition and behavioral symptoms with relevant disease predictors and with cognitive reserve (CR), quantified through education, physical activity, and occupation proxies. <i>Methods</i>: A prospective sample of 162 ALS patients and 61 controls were evaluated with the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) (dependent variable), a Cognitive Reserve Index questionnaire (CRIq) and demographic data (age and sex), and, for patients, clinical variables: disease duration, site of onset, the ALS Functional Rating Scale (ALSFRS), forced vital capacity (FVC), and gene mutation chromosome 9 open reading frame 72 (<i>C9orf72</i>) (independent variables). Multiple regression and mediation analyses were performed to predict cognitive and behavioral symptoms. <i>Results</i>: For the ALS group, the statistical model explained 38.8% of variance in ECAS total (<i>p</i> &lt; 0.001), 59.4% of executive functions (<i>p</i> &lt; 0.001), and 55% of behavioral symptoms (<i>p</i> &lt; 0.001). For controls, it accounted for 52.8% of variance in ECAS total (<i>p</i> &lt; 0.001). Interaction effects and mediation analysis showed CR is an ECAS total modulator, with a differential effect within groups (<i>p</i> &lt; 0.001). Verbal fluency was the single best cognitive score to differentiate patients from controls (<i>p</i> = 0.004), and the gene mutation <i>C9orf72</i> was found to be a behavioral symptom’ predictor in patients (<i>p</i> = 0.009). <i>Conclusion</i>: This study supports the proposed concept that CR acts as a cognitive modulator in ALS patients and healthy individuals. Moreover, CR also modulates behavioral manifestations in ALS.