ALS phenotype is influenced by age, sex, and genetics: A population-based study

Objective To assess the determinants of amyotrophic lateral sclerosis (ALS) phenotypes in a population-based cohort. Methods The study population included 2,839 patients with ALS diagnosed in Piemonte, Italy (1995–2015). Patients were classified according to 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 [ALScbi], ALS–frontotemporal dementia [FTD]). Binary logistic regression analysis was adjusted for sex, age, and genetics. Results Bulbar phenotype correlated with older age (p Conclusions Our data suggest that the spatial–temporal combination of motor and cognitive events leading to the onset and progression of ALS is characterized by a differential susceptibility to the pathologic process of motor and prefrontal cortices and lower motor neurons, and is influenced by age, sex, and gene variants. The identification of those factors that regulate ALS phenotype will allow us to reclassify patients into pathologically homogenous subgroups, responsive to targeted personalized therapies.