Aβ clearance from the brain is decreased in APP/E4 and APP/E4/Abca1−/+ mice. In vivo microdialysis was performed in the hippocampus of 4.5-month-old awake freely moving mice, and Aβ40 and Aβ42 concentration was determined by ELISA. Analysis is by two-way ANOVA followed by Bonferroni's posttest. A, Aβ40 level in ISF. There is no interaction between ApoE and Abca1. There is a main effect of Abca1 (p < 0.001) and ApoE (p < 0.001). p < 0.001 by Bonferroni's posttest. ***p < 0.001 by t test. N = 4–5 mice per group. B, Aβ42 level in ISF. There is an interaction between ApoE and Abca1 (p < 0.01); main effects of Abca1 (p < 0.001) and ApoE (p < 0.001). p < 0.001 by Bonferroni's posttest. ***p < 0.001 by t test. N = 4–5 mice per group. C, D, Aβ40 and Aβ42 half-life is increased in APP/E4 and APP/E4/Abca1−/+ mice. To determine ISF Aβ half-life, 1 h baseline samples were taken from hours 12–15 after probe implantation, and at the beginning of hour 16, animals were injected with γ-secretase inhibitor LY411575 (10 mg/kg). Aβ half-life was calculated by nonlinear regression analysis (one-phase exponential decay) as described in Materials and Methods. C, Aβ40 half-life is increased in APP/E4 and APP/E4/Abca1−/+ mice. There is no interaction between ApoE and Abca1; main effect of ApoE (p < 0.001) but not of Abca1. **p < 0.01 by t test. N = 4–5 mice per group. D, Aβ42 half-life is increased in APP/E4 and APP/E4/Abca1−/+ mice. There is no interaction between ApoE and Abca1; main effects of ApoE (p < 0.01) and Abca1 (p < 0.01). p < 0.05 by Bonferroni's posttest; *p < 0.05 by t test. N = 4–5 mice per group. Error bars indicate SEM.