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Enhancing cognition through the menopausal transition in at-risk 'APOE4' carriers by fatty acid and hormonal modulation.

Reference	BB/X002209/1
Principal Investigator / Supervisor	Prof. Anne-Marie Minihane
Co-Investigators / Co-Supervisors	Professor David Llewellyn, Dr David VAUZOUR
Institution	University of East Anglia
Department	Norwich Medical School
Funding type	Research
Value (£)	628,282
Status	Current
Type	Research Grant
Start date	03/04/2023
End date	02/04/2026
Duration	36 months

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.

Summary

Dementia is a group of symptoms associated with age-related decline in brain function. It affects memory, reasoning, communication, and mood. There are 850,000 in the UK living with dementia, with an expected rise to two million by 2050. As a result, the cost of dementia care in the UK is expected to more than double in the next 25 years. Alzheimer's disease (AD) is the most common form of dementia. Almost two-thirds of AD patients are women. The reason behind the higher female prevalence is thought to be related to the effects of menopause and the impact of the APOE4 genetic risk factor on brain function. Menopause is defined as the permanent cessation of ovarian function. The years leading up to menopause are called the menopausal transition, or perimenopause. This period is currently considered critical, where estrogen decline has been linked to a decline in brain (cognitive) functions. Limited recent studies suggest that the introduction of estrogen replacement therapy (ERT) during the menopausal transition could provide cognitive benefits to women at risk of AD. However, it is poorly understood and worthy of investigation to look at the impact and mechanism of action of ERT in the brain. Variation in our genes can affect our body's ability to produce functional proteins. This may subsequently change body metabolism and risk of diseases such as AD. Variation in the APOE gene results in three versions of the protein, namely E2, E3 or E4. We all have two copies of each gene and those of us who are APOE3/E4 (25% UK population) or APOE4/E4 (2% UK population) are at 3- and 15-fold increased risk of AD compared to those with the most common APOE3/E3 (60% UK population). Recent studies show that the risk of AD is higher in APOE4-women compared to APOE4-men, which begins during the menopausal transition. In mice and human studies, we and others demonstrated that the increased risk of AD in APOE4 females is likely due to increased brain inflammation and lower performance of the end of brain cells (neuronal synaptic regions), both of which affects the ability of brain cells to function properly which over time can lead to cognitive decline. The brain, and in particular the synaptic region, is rich in an omega-3 fatty acid found in oily fish, called DHA. In population observational studies and animal experiments increased DHA intake is associated with improved cognition and reduced AD risk. We hypothesise that DHA and estrogen replacement will together increase brain DHA levels, improve cognition and reduce dementia incidence in at-risk APOE4 females. We will test this by analysing dietary, hormonal, and cognitive test datasets of menopausal women from the UK BIOBANK. In addition, we will test the impact of dietary DHA and hormonal intervention on the cognitive function of our well-established menopausal mouse model. In the UK BIOBANK analysis, we will benefit from a large-scale database of half a million UK participants (of which 260,000 are females, with a follow-up period of 12 years+), to look at the individual and collective effect of DHA intake and status, hormone use, and APOE4 status on cognitive function, AD incidence, and brain volume. In the mouse model, we will feed mice that express the human APOE3 and APOE4 gene with DHA, then induce a human-like menopause and administer estrogen early or late during the menopausal transition. The cognitive function of the mice will be assessed, then the brain tissue will be extracted for evaluating brain integrity, and for gene, protein, and fatty acids profiling. From a public-health point of view, this study will help in identifying dietary and hormonal replacement strategies for at-risk APOE4 women (who represent about 13% of the general population but almost 40% of total AD patients) at a critical menopausal window. This can assist in improving the quality of life of older females and in reducing the rising national budget for dementia care.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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