Using distinct biomarker discovery and validation ante-mortem tissue cohorts, we provide evidence of pre-symptomatic TDP-43 pathology across diverse non-CNS peripheral tissues, including skin decades before ALS symptom onset, highlighting skin TDP-43 pathology as a potential early biomarker for ALS and related TDP-43 proteinopathies. Here, TARDBP is linked to amyotrophic lateral sclerosis.