Amyotrophic Lateral Sclerosis (ALS) is a severe and incurable neurodegenerative disease of motor neurons with a dramatic socio-economic impact on the national health system. ALS is a complex disorder with the majority of cases being sporadic and about 15% of cases showing familial history. It is characterized by high genetic heterogeneity, with more than 30 causative genes accounting for 60% of familial and 10% of sporadic cases. The clinical manifestations of ALS are variable with respect to age and site of onset, disease progression, relative upper versus lower motor neuron involvement, genetic background, and the occurrence of cognitive and behavioral change. This remains the case in those families with known disease-causing variants, suggesting that additional disease-modifying factors exist. A variety of wet biomarkers, including neurofilaments and extracellular vesicles, hold great promise in predicting the development of the disease and the variability in its progression. Neuroimaging techniques have been demonstrated to be able to detect abnormalities in motor and non-motor areas with a variety of patterns that reflect disease severity, progression, and duration. Disease heterogeneity is likely underpinned by the presence of different pathogenic mechanisms that can be studied at a molecular level in preclinical models. Human-induced pluripotent stem cells (iPSC) and derived motor neurons have shown functional disease-relevant phenotypes and seem to be particularly useful in modeling the heterogeneity of human ALS. All these pieces of information scattered in different studies have not been combined to drive research toward personalized medicine. In this project, the investigators gathered a team of exceptional and specific expertise in all these aspects of ALS research. The research group will perform an in-depth characterization of the clinical, neuroradiological, genetic, and biochemical levels of a cohort of ALS patients. In particular, researchers will measure selected established biomarkers mirroring fundamental pathophysiological processes in ALS such as neuroaxonal degeneration, alterations in protein homeostasis, TDP-43 pathology, neuroinflammation, and cell-cell communication. The investigators will also use neuroimaging techniques to highlight the structural and functional correlates of neurodegeneration in ALS. Next, researchers will integrate all these data by using artificial intelligence approaches with the aim of identifying different signatures that can be modeled in vitro in patient-derived iPSC. The investigators are confident that the PERMEALS project, by using a combined multi-angled approach, will represent the first step toward a personalized medicine to cure ALS.