Estradiol improves behavior in FAD transgenic mice that express APOE3 but not APOE4 after ovariectomy

Increasing evidence suggests that female individuals have a higher Alzheimer's disease (AD) risk associated with post-menopausal loss of circulating estradiol (E-2). However, clinical data are conflicting on whether E-2 lowers AD risk. One potential contributing factor is APOE. The greatest genetic risk factor for AD is APOE4, a factor that is pronounced in female individuals post-menopause. Clinical data suggests that APOE impacts the response of AD patients to E-2 replacement therapy. However, whether APOE4 prevents, is neutral, or promotes any positive effects of E-2 is unclear. Therefore, our goal was to determine whether APOE modulates the impact of E-2 on behavior and AD pathology in vivo. To that end, mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce A beta 42 were ovariectomized at either 4 months (early) or 8 months (late) and treated with vehicle or E-2 for 4 months. In E3FAD mice, we found that E-2 mitigated the detrimental effect of ovariectomy on memory, with no effect on A beta in the early paradigm and only improved learning in the late paradigm. Although E-2 lowered A beta in E4FAD mice in the early paradigm, there was no impact on learning or memory, possibly due to higher A beta pathology compared to E3FAD mice. In the late paradigm, there was no effect on learning/memory and A beta pathology in E4FAD mice. Collectively, these data support the idea that, in the presence of A beta pathology, APOE impacts the response to E-2 supplementation post-menopause.