Chiò A, Moglia C, Canosa A, et al. - In a population-based cohort, researchers evaluated the determinants of amyotrophic lateral sclerosis (ALS) phenotypes. Study participants involved 2,839 individuals with ALS diagnosed in Piemonte, Italy (1995–2015). Participants in the study were classified based on motor (classic, bulbar, flail arm, flail leg, predominantly upper motor neuron [PUMN], respiratory) and cognitive phenotypes (normal, ALS with cognitive impairment [ALSci], ALS with behavioral impairment [ALSbi], ALSci and ALSbi combined, ALS–frontotemporal dementia). The data indicate that differential susceptibility to the pathologic process of motor and prefrontal cortices and lower motor neurons is characterized by the spatial-temporal combination of motor and cognitive events leading to the onset and progression of ALS and is influenced by age, gender and gene variants. Identifying those factors that regulate the phenotype of ALS will enable us to reclassify patients into pathologically homogenous subgroups, responsive to targeted personalized therapies.