Some individuals with Alzheimer’s disease (AD) pathology exhibit cognitive resilience, offering promising prospects for identifying new therapeutic targets.Aims: Our hypothesis centers around the contribution of resilience to changes in excitatory synapses at the structural and molecular levels, which may underlie healthy cognitive performance in aged AD animals.Methods: We used Morris Water Maze tests, ELISA, western blots, stereological methods and immunoelectron microscopy.Results: Utilizing the Morris Water Maze test, we selected resilient (asymptomatic) and cognitively impaired aged-Tg2576 mice. While ELISA showed similar levels of Aβ42 between the two groups, western blots revealed differences in tau pathology in the pre-synaptic supernatant fraction. Using stereological methods at the electron microscopic level, our findings indicated a decrease in excitatory synapse density in the stratum radiatum of the CA1 field in impaired Tg2576 mice compared to age-matched resilient Tg2576 and non-transgenic controls (WT). In addition, the density of GluA1, GluA2/3, and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared to age-matched resilient Tg2576 and non-transgenic controls. Notably, the density of GluA2/3 in resilient Tg2576 was significantly increased in spines but not in dendritic shafts when compared to impaired Tg2576 and WT mice.Conclusions: These subcellular findings strongly support the hypothesis that spine plasticity and synaptic machinery play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.Grant PID2021-125875OB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and “ERDF A way of making Europe”, and Junta de Comunidades de Castilla-La Mancha (SBPLY/21/180501/000064)