Together, these findings indicate that mislocalized TDP‐43 is the leading cause of HDAC1 mislocalization, that HDAC1 is trapped in TDP‐43 aggregates and inclusions, and explain the observed reduction in nuclear HDAC1 levels, as well as no mislocalized TDP‐43 and HDAC1 can be detected at the early time of disease onset (2 months old of Tg mice, Tsai et al, 2010), indicating that HDAC1 dysregulation represents a second pathogenic wave contributing to cognitive deficits. This evidence concerns the gene HDAC1 and Cognitive impairment.