New evidence of pre-symptom changes during ALS development. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating related neurodegenerative diseases. There is a desperate need for ways to detect these diseases before symptoms develop. One of the hallmarks of ALS–FTD is aggregated abnormal TDP-43 after death, but if the changes in this protein occur sooner was unclear. Yet a recent study was able to detect signs of abnormal TDP-43 protein in pre-symptomatic ALS–FTD patients. Previous studies had suggested that normal splicing of some mRNA is suppressed in ALS–FTD, leading to the inclusion of additional code sections, called exons, which can produce new binding locations for antibodies called epitopes. So, the team developed a type of antibody test, called an ELISA, that could detect one of these ‘neo-epitopes’. With the ELISA, they were able to detect the loss of TDP-43 function in the cerebrospinal fluid of people with symptomatic familial ALS–FTD and sporadic ALS, and even in blood and cerebrospinal fluid from pre-symptomatic individuals with a familial ALS–FTD mutation. Overall, these findings suggest that loss of TDP-43 function does occur before symptom onset in ALS–FTD, and that the resulting cryptic proteins could potentially be used to detect these diseases sooner.