UK Parkinson's Disease Consortium

• Findings suggest immune response plays a key role in development of Alzheimer’s
• Results welcomed by Secretary of State for Health

Scientists have discovered 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. Led by scientists at UCL’s Institute of Neurology, the international team studied 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 findings, which are published in the New England Journal of Medicine on Wednesday 14 November, have the potential to be the most influential gene discovery for Alzheimer’s in the last two decades. Funders for the study included Alzheimer’s Research UK, the UK’s leading dementia research charity, the Medical Research Council (MRC) and the Wellcome Trust.

Huge advances in technology mean 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 precise 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. 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 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 that several mutations in the TREM2 gene occurred more frequently in people who had the disease than in those without the disease. One specific mutation, known as R47H, had a particularly strong association with the disease – appearing in 2% of people with Alzheimer’s compared to 0.5% of people without the disease. The scientists then confirmed their findings in two larger independent groups, analysing data from a total of 6,675 people with Alzheimer’s and 16,242 people without the disease. Again, 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 is extremely rare, affecting just 0.3% of the population, it increases the likelihood of developing Alzheimer’s roughly three-fold – more than any of the genes that have been linked to Alzheimer’s in the last 20 years. 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.

Dr Rita Guerreiro of UCL, the study’s lead author, said:
“These findings are particularly exciting because they give us a clear signal about what could be going wrong in Alzheimer’s disease. While the genetic mutation we found is extremely rare, its effect on the immune system is a strong indicator that this system may be a key player in the disease. The more we can understand about the causes of Alzheimer’s, the better our chances of developing treatments that could stop the disease developing.”

Prof John Hardy of UCL, a co-author on the study, said:
“This is the biggest study of its kind in Alzheimer’s to date, and it’s only been possible to achieve these results because researchers across the globe joined forces to tackle this problem. Thanks to new advances in technology it’s now possible to get a much more detailed look at the genetic risk for Alzheimer’s, picking up rare variants like this one that were previously impossible to identify. Some of the more common risk genes for Alzheimer’s are also involved in our immune response, and together these findings support an emerging theory that the immune system plays an important role in the disease.”

Health Secretary Jeremy Hunt said:
"This Government is committed to making the UK a world leader in dementia, and research of this kind has a vital role to play in helping to achieve this. Building a strong evidence base will help to improve our understanding of the disease, and achieve more for people living with dementia now and in the future."

Dr Eric Karran, Director of Research at Alzheimer’s Research UK, said:
“This is a landmark finding and reveals important new clues about the genetic causes of Alzheimer’s disease. We’re pleased to have supported this pioneering study, which will have major implications for understanding how Alzheimer’s develops – an important step towards designing new treatments. For these findings to live up to their potential and make a difference to people’s lives, it’s crucial that research building on this work continues and the role of the immune system in Alzheimer’s is fully explored. We look forward to funding more high quality research in this key area.”

Guerreiro, R. et al., 2012. TREM2 Variants in Alzheimer’s Disease. New England Journal of Medicine. Available at: http://dx.doi.org/10.1056/NEJMoa1211851 [Accessed November 15, 2012].

The research was carried out by collaborators at UCL (University College London), the Mayo Clinic, Jacksonville, FL; University of Toronto, US National Institute of Aging, Washington University School of Medicine, King’s College London, University of Nottingham, Brigham Young University, Tanz Centre for Research in Neurodegenerative Diseases, Istanbul University, Utah State University, University of Coimbra, Medical University of Lodz, University of Perugia, University of Kuopio, Aristotle University of Thessaloniki, Hospital La Grave-Casselardit, University of Manchester, Université Lille Nord de France, Cardiff University, University of Cambridge and NIH.