Understanding how genes related to the immune system contribute to Alzheimer's disease

Read about a research project investigating the functional characterisation of rare risk variants in immune genes associated with Alzheimer’s disease

Lead Investigator: Dr Angela Hodges

  • Institution: Institute of Psychiatry, King's College London
  • Grant type: PhD studentship
  • Amount: £85,000
  • Start date: October 2014
  • End date: September 2017

The background 

Research has shown that 1-3% of people with late onset Alzheimer’s disease have changes in two related genes – TREM2 and CSF1R - which are believed to contribute to the risk of developing the condition. 

This research group has identified several changes on each of these genes that they think increase the risk of developing Alzheimer’s disease.

These two genes code for structures in our cells which researchers think are important for controlling the activity of cells that play a role in the brain’s immune system and clearing away waste materials.

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. 

The researchers aimed to use these changes in the TREM2 and CSF1R genes to understand more about how these genes function and what goes wrong when these different versions of the gene are present in people who have increased risk of developing Alzheimer’s disease. 

What did the project involve?

The research team focused on exploring how changes to the TREM2 gene affected cells derived from a mouse model of Alzheimer’s disease. 

Dr Hodges wanted to find out how changes in the TREM2 gene affected the behaviour of the TREM2 protein which it codes for and the behaviour of the cell.

Secondly they used these cells and this information to screen for drug which might overcome these changes to the TREM2 protein and could have potential as a treatment for Alzheimer’s disease.

To confirm that these changes were also present in people with Alzheimer’s disease they also studied TREM2 in the cells and tissue of people with the condition.

What were the key results?

Dr Hodges and her team unfortunately were not able to replicate the exact changes to the TREM2 gene seen in people to the cell line however they were able to produce 4 cells lines with similar changes to the TREM2 gene.

They found that cells with these changes to TREM2 were more vulnerable and more likely to die in the presence of bacteria but were more responsive to treatment with antibodies (natural proteins in the body that fight infection) . 

The team think this increase in sensitivity might ultimately damage the cell.  

How will this benefit people with dementia?

It is important to establish how each of the Alzheimer’s disease-associated changes to our genes affects the function of the proteins they code for and how they contributes to disease. This is vital to give meaningful advice about risk to families who may have these changes and to identify treatments able to overcome vulnerability caused by them. 

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 other types of dementias.

Next steps

The PhD student Yau Mun Lim is looking to find postdoctoral positions to begin work studying post mortem brain tissue from people who had Alzheimer’s disease.

The cells models that were used in this project will continue to be used by other researchers in this lab to understand the role of TREM2 in Alzheimer’s disease and to identify potential new treatments. 

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