Gadd45 genes have been implicated in survival mechanisms, including apoptosis, autophagy,cell cycle arrest, and DNA repair, which are processes related to aging and life span. Here, weanalyzed if the deletion of Gadd45a activates pathways involved in neurodegenerative disorders suchas Alzheimer’s Disease (AD). This study used wild-type (WT) and Gadd45a knockout (Gadd45a−/−)mice to evaluate AD progression. Behavioral tests showed that Gadd45a−/− mice presented lowerworking and spatial memory, pointing out an apparent cognitive impairment compared with WTanimals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involvedin its phosphorylation in the hippocampus. Moreover, Gadd45a−/− animals significantly increased thebrain’s pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins andthe dendritic spine length of the neurons were reduced in Gadd45a−/− mice, which could contributeto the cognitive alterations observed in these animals. Overall, these findings demonstrate that thelack of the Gadd45a gene activates several pathways that exacerbate AD pathology, suggesting thatpromoting this protein’s expression or function might be a promising therapeutic strategy to slowdown AD progression.</p