Researchers from the University have helped uncover a second rare genetic mutation which strongly increases the risk of Alzheimer’s disease in later life.

The Translational Cell Sciences Human Genetics research group pinpointed a rare coding variation in the Phospholipase D3 (PLD3) gene which is more common in people with late-onset Alzheimer’s.

The discovery is a milestone on the road to early diagnosis of the disease and improved treatment. Having surveyed the human genome for common variants associated with Alzheimer’s, geneticists are now examining rare mutations for even stronger risk factors.

More than 820,000 people in the UK have dementia. The condition, of which Alzheimer’s disease is the predominant cause, costs the economy £23bn a year, much more than cancer and heart disease.

Nottingham’s genetic experts have been working with partners from Washington University, St Louis, USA, and University College, London, to carry out next-generation whole exome sequencing on families where Alzheimer’s affects several members.

The collaboration uncovered the first rare genetic mutation implicated in disease risk, linking the TREM2 gene to a higher risk of Alzheimer’s (published in the New England Journal of Medicine). Now, a new study in the journal Nature reveals how the team’s analysis of the genes of 2,000 people with Alzheimer’s revealed a second genetic variation, in the PLD3 gene.

PLD3 influences amyloid precursor protein. Amyloid plaques are characteristic of AD brain tissue and suggest a potential therapeutic target.

The international research team used Nottingham’s Alzheimer’s Research UK DNA bank, one of the largest collections of DNA from Alzheimer’s patients, to completely sequence the coding region (exome) of the PLD3 gene. The results showed several mutations in the gene occurred more frequently in people who had the disease. Carriers of PLD3 coding variants showed a two-fold increased risk for the disease.

Leading the team at Nottingham, Professor of Human Genomics and Molecular Genetics Kevin Morgan said: “Our research is forming the basis of potential diagnostics and more importantly it shows pathways that can be diagnostic targets which could lead to therapeutic interventions. The next step is examining how this particular rare gene variant functions in the cell and see if it can be targeted, to see if there are any benefits to finding out how this gene operates in both normal and diseased cells. If we can do this, we may be able eventually to correct the defect with drug therapy.

“Even if we could eventually slow or halt the progress of the disease with new drugs rather than curing it completely, the benefits would be huge in terms of the impact on patients’ lives and also in vast savings to the health economy. The University of Nottingham has played a significant role in all of the recent AD genetics discoveries that have highlighted 20 new regions of interest in the genome in the last five years and we will continue to do so.”