APP/PS1;C3 KO mice showed a significant improvement in cognitive flexibility (reversal) compared to APP/PS1 mice at 16 months of age. A. Percent of mice that reached criterion (≥ 80% correct choices on each individual day) in WTM test. Compared to WT mice, APP/PS1 mice were impaired in acquisition (Days 2) and reversal learning and memory (Days 4 and 5) (*p < 0.05; ** p < 0.01). APP/PS1;C3 KO mice performed significantly better than APP/PS1 mice (## p < 0.01), but similar to WT and C3 KO mice, in the reversal test on Days 4 and 5, suggesting better flexibility in APP/PS1;C3 KO mice compared to APP/PS1 mice. B. In total, fewer APP/PS1 mice reached the reversal criterion (≥80% correct choices over two consecutive days) (*p < 0.05), while the percent of WT, C3 KO and APP/PS1;C3 KO mice that reached criterion in the reversal test was significantly higher compared to APP/PS1 mice (***p < 0.001), indicating that C3-deficiency in APP/PS1 mice had both age-dependent and AD-related effects (WT, n=13; APP/PS1, n=11; APP/PS1;C3 KO, n=10; C3 KO, n = 11). Tests were assessed using one-way ANOVA followed by Fisher’s PLSD post hoc test.