APOE4 genotype exacerbates the impact of menopause on cognition and synaptic plasticity in APOE‐TR mice

The impact of sex and menopausal status in Alzheimer’s disease remains understudied despite increasing evidence greater female risk, particularly APOE4 carriers. Utilizing APOE-TR mice maintained on a high-fat diet background we induced ovarian failure through repeated VCD injections, to mimic human menopause. At 12 months age, recognition memory spatial were assessed using object recognition, Y-maze spontaneous alternation, Barnes maze. A VCD*genotype interaction reduced the (P < .05), with VCD-treated animals unable distinguish between novel familiar objects. displayed an additional 37% 12% reduction .01) performance, indicative genotype-specific impairment. Molecular analysis indicated both genotype-related deficits synaptic plasticity BDNF, Akt, mTOR, ERK signaling compromised. Subsequent reductions transcription factors Creb1 Atf4 also evident. Furthermore, specifically diminished Ephb2 expression, while Fos, Cnr1 expression as consequence genotype. Brain DHA levels 13% lower independent Consistent this, detected alterations transporters Acsl6 Fatp4. Our results indicate that combination leads exacerbation cognitive neurological deficits.