Lead Investigator: Dr Angela Hodges
Institution: Institute of Psychiatry, King's College London
Grant type: PhD studentship
Duration: 3 years
Scientific Title: Functional characterisation of rare risk variants in immune genes associated with Alzheimer's disease
Why did we fund this project?
Comments from members of our Research Network:
'An important contribution to the ongoing research into causes and possible prevention of Alzheimer's disease. A solid programme which offers benefits to all concerned.'
'This appears to be a promising line of research in which collaboration with scientists working on other neurodegenerative disorders such as Parkinson's disease could be mutually advantageous.'
'Any work that is able to identify people susceptible to Alzheimer's is particularly useful, and this one with the potential to identify particular gene changes would seem to be particularly worthwhile.'
What do we already know?
Recent research has shown for the first time that 1-3 percent of people with late onset Alzheimer's disease have changes in two related genes – TREM2 and CSF1R - which are believed to significantly contribute to their vulnerability to developing disease.
This research group has identified several changes on each of these genes that they think increase the risk of developing Alzheimer's disease, and they need further proof that they do indeed put people at risk of developing disease.
These two genes code for receptors (structures on the outside of cells which connect with other proteins and control certain actions and responses), which are believed to be very important for controlling the activity of cells that play a role in the brain's immune system and clearing away waste materials. They may also be very important for maintaining other brain cells in a healthy state. This fits with the growing evidence that the immune system is not only compromised in Alzheimer's disease but may even contribute to its development.
These genes appear to be at the centre of the brain's immune system, which may be affected in the majority of people who have Alzheimer's disease regardless of whether or not they have an altered version of these genes. We don't yet know enough about what these genes do to understand their contribution to disease.
It is already known that changes elsewhere in these two genes can cause rare neurological conditions. This provides some clues about what these receptors do and how their normal activity may be altered to cause disease and the symptoms people experience.
The researchers will use these newly identified changes in the TREM2 and CSF1R genes to increase our understanding of how these genes function and understand what goes wrong when these different versions of the gene are present in people who have increased risk of developing Alzheimer's disease. They aim to then apply this knowledge to screen for potential drugs that are able to overcome these changes or boost the normal activity of these two genes to offer protection for all people with Alzheimer's disease, even those without the changes in the gene.
What does this project involve?
The researchers will create cells within the lab with each of the identified changes on these genes. They will compare the effects of their over- and under-production in cells and measure the impact on things that are affected and likely to contribute to Alzheimer's disease. They will also assess what aspects of cell function are affected.
They will test the ability of normal cells and those with the changes to respond to things that are known to be required for the normal function of these genes and measure the impact.
The researchers will then test whether the things they have measured are also altered in the brains and blood of people who have changes in these genes which cause or contribute to their disease.
How will this benefit people with dementia?
It is important to establish how each of the Alzheimer's disease-associated changes affect normal function of these genes and understand how each of them contributes to disease, in order to give meaningful advice about risk to families who may have these changes and to identify treatments able to overcome vulnerability caused by them.
As these changes represent genetic vulnerability to disease the potential will be that any treatment would be able to go beyond symptomatic treatment to enable the possibility of preventing disease emerging in the first place in affected people. It will also allow at-risk people to have a genetic test if they wish, so that they can make informed choices about their future and seek the right support, which will be particularly important once a treatment becomes available. This will be very similar to what is currently available for families who have a rare inherited form of early onset Alzheimer's disease, for which a diagnostic gene test and genetic counselling are already available.
A better understanding of what these genes do is not only vital for the families who have an altered version of the gene but is also likely to be relevant to all people who develop Alzheimer's disease and related dementias.