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

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.