Project Summary/Abstract We propose to study the relation between blood concentrations of persistent organic pollutants (POPs) and amyotrophic lateral sclerosis (ALS) incidence and survival using blood samples collected well before the onset of ALS. We will also explore whether those exposures, and ALS, are associated with changes in extracellular vesicles (EV) derived specifically from immune system cells to identify mechanisms related to the exposures, ALS, and associations between them. We will conduct a case-control study nested within large prospective cohort studies in Denmark and Finland that total almost 120,000 participants. The participants provided blood samples at the cohort baselines, and we identify ALS cases during follow-up via linkage with National registries. We anticipate a total of 265 ALS cases that occurred after cohort enrollment. We will randomly select 2 controls per case individually matched on age, sex, and cohort from among all non-ALS cases alive at the time the case is diagnosed. Extensive questionnaire data from the cohorts is available for regression model adjustments. The blood samples will be analyzed for organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). EVs will be isolated and characterized in terms of size and number, and percentage expressing specific surface markers that identify EVs derived from cells of the immune system. By nesting this study within large Danish and Finnish prospective cohort studies that have blood samples from many years before ALS, we have a unique setting that will allow us for the first time to assess the relation between toxicant exposures and ALS using individual biomarkers of exposure from samples collected before ALS onset, thereby avoiding problems associated with questionnaire recall of past exposures or biomarker measurements in samples collected after ALS onset that may be affected by disease (leading to possible reverse causation). The pre-disease biosamples also allow us to explore biological mechanisms that may underlie the associations we see and possibly identify biomarkers of future disease risk and survival, thereby providing insight into ALS pathophysiology.