The University of Nottingham

Researchers from Nottingham have played their part in the discovery of a rare genetic mutation that increases the risk of Alzheimer’s disease, in a study with major implications for understanding the causes of the disease.

The international team, which involved a research team led by Kevin Morgan, Professor of Human Genomics and Molecular Genetics at The University of Nottingham, used data from more than 25,000 people to link a rare variant of the TREM2 gene — which is known to play a role in the immune system — to a higher risk of Alzheimer’s.

The discovery is the first so-called ‘Goldilocks’ variant associated with Alzheimer’s Disease, because it’s prevalence is ‘just right — it’s common enough to be identified in large populations but rare enough to point to a genetic mutation that potentially could have a significant role in identifying risk factors for the disease.

Professor Morgan said: “This research has identified the first ‘Goldilocks’ variant in Alzheimer’s Disease — one whose effect is spot on, not too big or too small, just perfect for this type of approach to identify.

“The risk associated with this new variant is the largest seen to date and heralds the start of a new era in AD genetic research. At long last we are beginning to witness major breakthroughs that will hopefully result in therapeutic developments to help alleviate this devastating condition.”

The findings of the research, which are published in the New England Journal of Medicine on Wednesday November 14, suggest that problems with the immune system could be a key player in the development of Alzheimer’s.

Funders for the study included Alzheimer’s Research UK (ARUK), the UK’s leading dementia research charity, the MRC and the Wellcome Trust.

The causes of Alzheimer’s are still unknown, but the disease is likely to be caused by a complex mix of genetic and environmental factors. While some genes that increase the risk of Alzheimer’s have been discovered, these discoveries do not explain all of the genetic risk — but recent advances in technology means it’s now possible to study genes in much more detail, picking up rare mutations of genes that could not be found through other methods. The researchers set out to uncover some of the rarer genetic variants involved in Alzheimer’s, in a bid to get a clearer picture of the causes of the disease.

The international collaboration, led by scientists at University College London’s Institute of Neurology, used the Nottingham ARUK DNA bank, one of the largest collections of DNA from Alzheimer’s patients, to completely sequence the entire coding region (exome) of their genes.

The researchers began by sequencing the genes of 1,092 people with Alzheimer’s and a control group of 1,107 healthy people. The results showed several mutations in the TREM2 gene occurred more frequently in people who had the disease than in non-sufferers. One specific mutation, known as R47H, had a particularly strong association with the disease — appearing in 2 per cent of people with Alzheimer’s compared with 0.5 per cent of people without the disease.

The scientists then sought to confirm their findings in two larger independent groups, carrying out a meta-analysis of data from 5,541 people with Alzheimer’s and 13,408 people without the disease, as well as directly genotyping the genetic variant in another 1,134 people with Alzheimer’s and 2,834 people without the disease. In both instances, they found that the R47H variant was more likely to appear in people affected by Alzheimer’s than in people without the disease.

While this mutation increases the likelihood of developing Alzheimer’s roughly three-fold, it is extremely rare, affecting just 0.3 per cent of the population. But by identifying the mutation, the research provides valuable new information about the potential causes of Alzheimer’s disease.

The TREM2 gene controls a protein that is involved in regulating the immune response to injury or disease, acting as an ‘on/off switch’ for immune cells in the brain called microglia. The R47H variant of the gene results in a partial loss of this function, with less ability to keep these cells’ activity in check — potentially causing them to become hyperactive. The researchers now want to find out more about the role of TREM2 and better understand the effects of the R47H variant.