Sussex Doctoral Training Centre

Research project: Of Molecules, Mice and Men: exposing and understanding apolipoprotein E effects across the lifespan

Research project: Of Molecules, Mice and Men: exposing and understanding apolipoprotein E effects across the lifespan

Lead supervisor: Professor Louise Serpell
Additional supervisors: Professor Jennifer Rusted, Professor Gordon Harold, Dr Chris Bird, Dr Sarah King, Professor John Atack, Dr Kevin Staras
Grant type: Doctoral Training Centre
Amount: £350,000

Why did we support this? Comments from our Research Network:

'An interesting proposal linking together various strands of research in a coherent way.'

'[It's] a useful piece of research which could help identify people at risk of Alzheimer's.'

'This interdisciplinary project has much potential and the team appears well placed to achieve some meaningful outcomes.'

What is a Doctoral Training Centre? 

Alzheimer's Society Doctoral Training Centres (DTC) aim to create a cluster of PhD students and clinical fellows working on themed area of dementia research. In addition to generating new knowledge on the theme, the DTCs will also provide support and training to develop the next generation of dementia research leaders

What do we already know?

Most cases of Alzheimer's disease are not caused by strong genetic links, and are known as 'sporadic' Alzheimer's disease; the underlying cause is a mixture of genetics, environmental and other factors. However, there are genes that have been identified that increase the risk of developing the disease. The gene that has the strongest effect is called APOE4.

You inherit two versions of the APOE gene (one from each parent) and there are three different types that you can have: APOE2, 3, or 4. Up to 20 per cent of people have at least one copy of APOE4, so it is fairly common, but having one or more copy can increase the risk of developing dementia by 4-10 times.

Despite this, we still don't fully understand the role that APOE4 plays in developing Alzheimer's disease, and the effects that it has on our brains throughout life. We do know that Alzheimer's disease may begin to affect the brain many years before symptoms occur, so looking at people at various ages will help us to understand when these changes start to occur and how we may be able to stop them.

Understanding the differences between people with the gene who do not develop Alzheimer's disease compared with those who do is also important for our understanding of the role that this gene plays.

What will the projects in this DTC investigate?

In this DTC, PhD students will investigate the role that APOE4 plays in our brains' functions throughout life, to better understand the role that it plays in our brains, and in the development of Alzheimer's disease in later life.

One of the projects will look at education, and whether education has different effects on Alzheimer's disease risk for people with APOE4 compared to those with other types. High education is typically seen as protective against the symptoms of dementia, as it's thought that the brain is better able to compensate for the underlying changes occurring in the disease (this is known as 'cognitive reserve'), but it's uncertain whether this effect is also seen in people with APOE4 or whether other changes happen and actually increase the chance of developing Alzheimer's disease in these people.

Another project will use mouse models with either APOE3 genes or APOE4 genes to study the effects and differences of these across the whole lifespan. This will be investigated using memory and thinking tests to see at what point a difference is seen.

Another project will look at the role that the protein ApoE4, made by the APOE4 gene, plays in cells in a part of the brain crucial to learning and memory, called the hippocampus. The hippocampus is often one of the first areas to be affected in Alzheimer's disease. The project will look at whether there are differences in how efficiently the cells in the hippocampus work with ApoE3 and ApoE4, looking for explanations for any differences seen in the performance of mice in certain tasks in the above PhD students' work. This project will also investigate if having ApoE4 instead of another type of ApoE makes these cells more susceptible to the effects of toxic clumps of the protein amyloid, which are a hallmark of Alzheimer's disease.

The different types of APOE gene make proteins, also called ApoE, that are all slightly different in their shape. It may be that these slight differences are the cause of the underlying risk of Alzheimer's disease that ApoE4 brings. The fourth area of investigation within this DTC will build on the information from the other projects to work towards better understanding of differences in the function of the proteins produced by the genes, and develop drugs that may compensate for this.

How will this benefit people affected by dementia?

The causes of Alzheimer's disease are still not well understood and by investigating the role of one of the main genetic contributors to the disease it is hoped that researchers will better understand the underlying changes that cause Alzheimer's disease. This understanding is needed in order to develop better treatments or prevention methods in the future.

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