Abstract

Two-thirds of Alzheimer’s disease (AD) patients are females. Loss of estrogen during the menopausal transition is thought to drive an accelerated neuropathology and cognitive decline and underpin the higher AD prevalence in females. We recently showed in mice, that menopause and an APOE4 genotype (25% UK population) diminished object recognition and spatial memory, and reduced brain DHA, an omega-3 fatty acid which is highly enriched in brain tissue with well-defined structural and functional roles. Here using a longitudinal cohort analysis and a transgenic rodent intervention, we will determine the ability of early hormone and omega-3 fatty acid intervention, to mitigate the accelerated neurocognitive decline associated with menopause in female APOE4 carriers. Using the UK BIOBANK (approximately 260,000 women, 12y+ follow-up) the association between estrogen replacement therapy (ERT), DHA intake and status, and cognition and dementia incidence will be established in a large UK cohort. This will be complemented by a rodent dietary and hormonal intervention in our well-established APOE3- and APOE4- TR menopausal mouse model to provide physiological, biochemical, and molecular mechanistic insight, with a focus on BBB function, the concentration of DHA and its metabolites (oxylipins) and brain’s bioenergetic pathways. Cognitive decline and menopause are associated with a shift from glucose to fatty acids as a source of energy. BBB integrity will be assessed, using a fluorescein extravasation assay and immunochemistry, and the expression of select BBB tight junction proteins and fatty acid transporters. Bioenergetic pathways will be characterised by transcriptomic approaches. Brain fatty acids and anti-inflammatory oxylipins will be measured using gas chromatography and mass spectrometry.