Alzheimer's disease (AD) is a neurodegenerative disorder characterized by Amyloid β (Aβ)-driven synaptic dysfunction in the early phases of pathogenesis. However, cytoskeletal abnormalities, such as cofilin-actin rods, have been described in AD patients. In addition, we demonstrated that the actin-binding protein Cyclase-associated protein 2 (CAP2) is a master regulator of cofilin synaptic localization through the Cys32-dependent CAP2 dimerization. The CAP2 dimer-mediated cofilin translocation is required for synaptic plasticity-driven spine remodelling.This mechanism is altered in AD since CAP2 is downregulated and thereby, the synaptic availability of CAP2 dimer is decreased.Therefore, this work aimed to assess whether enhancing the expression of CAP2 could prevent cofilin pathological alterations in AD. To this aim, we used AAV-mediated gene transfer to overexpress CAP2 into the hippocampal neurons of AD mice to explore the effects on AD pathological traits.We showed that overexpression of CAP2 prevents cognitive decline, rescued CAP2/cofilin complex at the synapse and ameliorated actin rods formation. Taking advantage of neuronal cultures, we found that CAP2 is a component of mature cofilin-actin rods specifically induced by Aβ oligomers. Moreover, the complex CAP2/cofilin is an early target of Aβ oligomers, which affect CAP2 dimerization and association to cofilin. Furthermore, it turned out that CAP2 dimerization is essential to prevent Aβ-induced dendritic spine loss but not to protect from cofilin-actin rods formation.Our results suggest that enhancing CAP2 levels may improve synaptic function, reduce abnormal cofilin-actin rods formation and delay cognitive decline in AD, indicating that CAP2 can be a therapeutic target for AD.