Effect of 17α-Estradiol on Spatial Learning and Memory in APOE4 and 5xFAD Mice: Examination of Sex, Treatment, and Genotype

Alzheimer’s disease (AD) is the leading cause of dementia, with increasing prevalence among women. Age, sex, and the apolipoprotein E4 (APOE4) allele are major risk factors for late-onset AD. APOE4 is associated with accelerated cognitive decline and structural brain changes, while age-related sex hormone loss may exacerbate cognitive impairment in females. Although 17β-estradiol (17βE2) supports neuroplasticity, its peripheral effects limit therapeutic applications. Alternatively, 17α-estradiol (17αE2) has demonstrated neuroprotective potential in AD mouse models. This study investigated the cognitive effects of 17αE2 in 7–9-month-old male and ovariectomized female APOE3, APOE4, and 5xAD mice using the Barnes maze. Mice completed four training days followed by a 72 h probe trial assessing long-term spatial memory. Male and female 5xAD mice exhibited impaired spatial learning, with treatment and training day effects. Male APOE4 mice showed genotype and treatment × training day interactions, while females demonstrated treatment and training day effects. Both sexes of APOE4 mice exhibited increased primary errors during the probe trial without significant treatment effects. 17αE2-treated APOE4 mice showed reduced primary latency, suggesting potential treatment benefits, whereas female APOE4 mice exhibited increased latency. These findings highlight APOE4-associated spatial memory deficits and warrant further investigation of 17αE2 as a potential therapeutic intervention for AD-related cognitive impairment.