Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disorder with a widespread cortical disease signature. ALS patients demonstrate global network alterations in the white matter connectome in the early stage of disease. Selective disruption of cortical motor associated nodes with the thalamus and contralateral motor cortices is present at disease onset. Disease duration is associated with reduced structural interhemispheric cortical motor connectivity. Focal motor abnormalities present in the white matter connectome may be a sensitive marker in the earliest stages of ALS prior to functional decline.