Faulty X chromosome gene linked to dementia

A team from the Mayo Clinic College of Medicine in Jacksonville, Florida, US, has discovered a new gene variant that seems to increase the risk of developing Alzheimer's disease. The discovery is the first evidence of gender-specific risk factor for the disease because the variant is on the X chromosome, of which females have two copies, but men have only one. The results were published online in the journal Nature Genetics, and may partly explain why more women than men tend to develop the disease.

Alzheimer's disease is a progressive neurodegenerative disorder, characterised by personality changes and loss of memory, which eventually leads to death. The most common form, known as 'Late-onset Alzheimer's disease' (LOAD), affects approximately 700,000 people in the UK.

The Mayo team carried out a two-stage study involving detailed genetic analyses of nearly 5000 people, who were either Alzheimer's patients or unaffected control subjects. The study identified a suspect 'single letter' change in the genetic code of the gene PCDH11X that was significantly correlated with susceptibility to LOAD. The gene PCDH11X controls production of a protein called a protocadherin, part of a family of molecules that promote cell adhesion and signalling in the central nervous system.

When compared to non-carriers, the raised risk of Alzheimer's in people with the PCDH11X variant was relatively small in men (18 per cent increased risk) and women with just one copy of the rogue gene variant (26 per cent increased risk). The effect was most pronounced in women who carried two copies - one inherited from each parent - who have a 75 per cent increased risk over female non-carriers. To put this in context, a mutation in the well-known and previously studied APOE 4 gene was judged to increase risk in the Mayo group subjects by 380 percent if they carried one copy and 1050 per cent if they carried two copies.

'Although the presence of the mutation offers strong evidence of a heightened risk, further research needs to be done to determine how big of a risk', said Dr Steven Younkin, the George M. Eisenberg professor of neuroscience at the Mayo Clinic. He added: 'It is important to analyse many additional Alzheimer's disease cases and controls before drawing any final conclusions about the strength of the association and the degree of risk it confers on developing Alzheimer's disease'.