Project summary/abstract Amyotrophic lateral sclerosis (ALS) is a universally disabling and fatal neurological condition. Current treatments have only modest benefit. Development of effective therapeutics is hampered in part by inadequate knowledge of ALS natural history. Though valuable, existing ALS registries have either large samples sizes but limited clinical information, focus on relatively small subsets of the ALS population, or provide information from a relatively brief period. However, as a part of routine clinical care, ALS multidisciplinary clinics (MDCs) develop a rich natural history dataset from all ALS patients, and most people living with ALS are seen at MDCs. We have built a combined, de-identified natural history dataset from over 1,700 ALS patients from 9 MDCs, with racial representation that is reflective of the ALS population at large and broad geographic representation as well. We offer enrollment to all patients at our clinics. We will build on our multicenter, longitudinal, prospective MDC dataset in collaboration with industry and the ALS patient community to provide information critical for clinical trial development and post-marketing evaluation. Specifically, we will do the following: record clinically relevant baseline characteristics and serum neurofilament light (NfL) measurements at enrollment as well as validated longitudinal measures of disease progression including ALSFRS-R and disease staging, respiratory vital capacity, speaking rate and 10 meter walk test (Aim 1), record disease milestones based upon patient-reported outcomes, durable medical equipment orders in the electronic health record, and other events such as dates of gastrostomy, hospitalizations, and death (Aim 2), and model time to events using baseline characteristics as well as retrospective and prospective longitudinal data (Aim 3). We have demonstrated the ability to enroll the vast majority of patients seeking care in our clinics so as to best represent the ALS population. Baseline characteristics will include ALS phenotype and results of genetic testing. Datasets will be made available to academic and industry investigators to advance ALS care, drug development, and outcomes research. We will expand existing engagement from industry and other stakeholders to include an advisory panel of people living with ALS and will encourage opportunities for data dissemination through these existing relationships and publications.