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<i>Gadd45</i> 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, we analyzed if the deletion of <i>Gadd45a</i> activates pathways involved in neurodegenerative disorders such as Alzheimer’s Disease (AD). This study used wild-type (WT) and <i>Gadd45a</i> knockout <i>(Gadd45a^−/−)</i> mice to evaluate AD progression. Behavioral tests showed that <i>Gadd45a^−/−</i> mice presented lower working and spatial memory, pointing out an apparent cognitive impairment compared with WT animals, accompanied by an increase in Tau hyperphosphorylation and the levels of kinases involved in its phosphorylation in the hippocampus. Moreover, <i>Gadd45a^−/−</i> animals significantly increased the brain’s pro-inflammatory cytokines and modified autophagy markers. Notably, neurotrophins and the dendritic spine length of the neurons were reduced in <i>Gadd45a^−/−</i> mice, which could contribute to the cognitive alterations observed in these animals. Overall, these findings demonstrate that the lack of the <i>Gadd45a</i> gene activates several pathways that exacerbate AD pathology, suggesting that promoting this protein’s expression or function might be a promising therapeutic strategy to slow down AD progression.