Identify and Evaluate Potential Risk Factors for Amyotrophic Lateral Sclerosis - A Unique Contribution from Sweden

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Project summary Military service, traumatic brain injuries (TBI), chronic neuroinflammation and infections have all been suggested as potential risk factors for amyotrophic lateral sclerosis (ALS). The currently existing knowledge base is however limited by systematic and random errors. Moreover, the underlying mechanisms linking together those risk factors and the initiation and progression of ALS are still largely unknown. With the ultimate goal of providing important new knowledge for disease prevention among high-risk individuals and identifying novel therapeutic targets, the overarching aim of this research program is to use the extensive data and biospecimens collected in a unique Swedish national ALS registry, to identify and evaluate military service, TBI, mental disorders (as a proxy for chronic neuroinflammation), and infections as potential risk and prognostic factors for ALS, focusing on understanding their interactions with individual genetic susceptibility to ALS, chemical exposures (>10,000 chemicals and their metabolites measured in human tissue), and gut microbiome. We will replicate some of these findings in the Agency for Toxic Substances and Disease Registry (ATSDR) implemented US National ALS Registry where we have already collected samples from ALS patients. In the specific Aim I, we will assess the roles of military service, TBI, mental disorders and infections on the risk and prognosis of ALS, using prospectively and independently collected data from the Swedish national health registers (including the Motor Neuron Disease [MND] Registry), by contrasting ALS patients of different clinical phenotypes with three control groups, namely disease-free full siblings, spouses, and age- and sex-matched population controls. In the specific Aim II, we will characterize the role of interactions between different exposures and 1) individual genetic susceptibility to ALS, 2) chemical exposures, and 3) gut microbiome on ALS in Sweden and replicate findings in the United States. In the specific Aim III, we will develop a molecular phenotyping-based precision medicine tool to allow precise stratification of ALS patients based on their exposome, genetic susceptibility to ALS, and clinical measures, to provide a novel approach to better predicting disease progression. Findings from this project are expected to advance our understanding of ALS as a disease and provide new knowledge for disease prevention and treatment, fully supporting the ATSDR National ALS Registry's mission. The findings will also help ATSDR better prioritize topics for future research initiatives and inform the development of new ATSDR ALS Registry risk factor surveys for persons with ALS.