Here, we employ two of these recently developed tools, TDP-43apt in conjunction with STMN-2 cryptic exon BaseScopeTM probe, to investigate address two crucial questions in ALS, i.e., (i) what is the extent of pre-symptomatic TDP-43 pathology detectable in an ante-mortem cohort of people who went on to develop ALS, and (ii) can we identify and validate a particular peripheral tissue as a biomarker with greatest potential for clinical applications to identify early TDP-43 pathology prior to disease symptom onset. This evidence concerns the gene TARDBP and amyotrophic lateral sclerosis.