Deletion of apoE4 in neurons prevented the development of spatial learning and memory deficits in aged mice. A, Seventeen-month-old female apoE3-fKI, apoE4-fKI, apoE3-fKI/Syn-1-Cre, and apoE4-fKI/Syn-1-Cre mice were tested in the MWM. Points represent averages of daily trials. H, hidden platform day (2 trials per session, 2 sessions per day); H0, first trial on H1; V, visible platform day (1 trial per platform location, 3 sessions per day). Escape latency (y-axis) indicates time to reach the target. In the hidden platform days, latencies of all groups of mice were analyzed and compared by repeated-measures ANOVA and Bonferroni post hoc test. ApoE4-fKI mice learned significantly slower than apoE3-fKI mice (p < 0.01). ApoE4-fKI/Syn-1-Cre mice learned as well as apoE3-fKI mice (p > 0.05), which was significantly faster than apoE4-fKI mice (p < 0.001). There was no significant difference between apoE3-fKI and apoE3-fKI/Syn-1-Cre mice. B, Swim speed was similar among the four groups of mice. C–E, Probe 1, 2, and 3 trials were performed 24, 72, and 120 h, respectively, after the last day of hidden platform training. Percentage time spent in the target quadrant and the average percentage time spent in other three quadrants were compared for each group of mice. **p < 0.01, ***p < 0.001 (one-way ANOVA and Bonferroni post hoc test).