Identifying new risk genes for Alzheimer’s disease by studying inherited forms of dementia

Lead Investigator: Dr Rita Guerreiro 

Institution: University College London

Grant type: Senior Fellowship

Duration: 48 months

Amount: £399,986

Scientific Title: Exome sequencing in dementias - more than a family business

Why did we fund this project?

Comments from members of our Research Network:

'I feel this is an important research project that will further the understanding ofdementia. I feel it builds on previous research and will push the field forward'

'The prospect of identifying genes that could account for problems across several conditions and then being able to focus funds and research effort in these areas sounds very attractive'

'Needed research which includes a focus on some of the more rare forms of dementia'

What do we already know?

The genetics that lie behind the risk of developing dementia are complex. In the case of the most common form of Alzheimer's disease, there is only one gene that is known to strongly increase risk of developing dementia, which is called APOE. However, the APOE gene is not the whole story and researchers believe that there are many other genes that can influence dementia risk.

Dr Guerreiro and her team have previously identified another gene, called TREM2, which has rare changes that can also influence the risk of developing Alzheimer's disease. The discovery of TREM2 as an Alzheimer's risk gene was achieved by first identifying the involvement of the gene in rarer causes of dementia. The researchers then searched for similar changes in this gene in people with Alzheimer's disease. 

Evidence shows that there are many different aspects that can influence dementia risk, including the damage to blood vessels (also known as the vascular system) and the role of the immune system. Dr Guerreiro has already fostered collaborations with researchers who study particular families with genetic links to rare dementias and who also have symptoms involving the immune or vascular systems. 

What does this project involve?

Dr Guerreiro has already collected data from a family group with a rare disorder that affects brain function and can also lead to strokes. She will also investigate the genes of other families who have conditions that affect the brain or nerves alongside immune or vascular symptoms.  

The project will use a method called whole-exome sequencing. This technique involves searching a large amount of a person's DNA to identify small genetic changes. This project will discover whether a person who is affected by these rare conditions has genetic changes that are not seen in their unaffected family members. Dr Guerreiro and her collaborators will use this knowledge to determine which genes to search for in a wider population sample. They will compare the makeup of their selected genes in people with Alzheimer's disease to those who are not affected to find out whether there are any changes that are linked to disease development.  

How will this benefit people with dementia?

Gaining an understanding of the genetics behind a disease helps researchers to understand the mechanisms behind how and why a disease develops. For example, the TREM2 gene is involved in the immune pathway; therefore the discovery of TREM2 as an Alzheimer's risk gene has added to increasing evidence that the immune system may be involved in Alzheimer's development.

Identifying risk genes also allows researchers to investigate these genes and their associated mechanisms as potential targets for the development of new treatments for the related conditions. 

Understanding changes in genes will also help to clarify diagnosis of certain conditions, which will be particularly helpful in families affected by rarer forms of dementia that may have overlapping symptoms with other conditions. This will allow these families to access the support and treatments that are best suited for their particular condition.