Gene on X chromosome could increase women's Alzheimer's disease risk

A gene which is expressed more in women than men could offer a clue as to why women are at greater risk of developing Alzheimer's disease.

Females have two X chromosomes, one of which is inactivated in each cell, meaning the genes on it are not expressed. This helps stop genes that are present on both X chromosomes being overexpressed in women. However, a subset of genes can escape the inactivation of the chromosome including one that codes for an enzyme called USP11. Scientists from Case Western Reserve University in Cleveland, Ohio have determined this enzyme plays a role in the regulation of the tau protein in neurons, which is known to accumulate in the brains of people with Alzheimer's disease and frontotemporal lobe dementia.

'When a particular tau protein is no longer needed for its nerve cell's function, it is normally designated for destruction and clearance,' said Dr David Kang, co-author of the study. 'Sometimes this clearance process is disrupted, which causes tau to pathologically aggregate inside nerve cells. This leads to nerve cell destruction in conditions called tauopathies, the most well-known of which is Alzheimer's disease.'

Researchers found USP11 prevents tau from being degraded in the cell. This allows tau to clump together leading to the formation of 'tau tangles' which are seen in people with Alzheimer's disease, and cause the death of neurons. They have proposed in a study, published in the journal Cell, increased expression of this enzyme in women could increase the risk of developing Alzheimer's disease.

Post-mortem human brain tissue from patients with Alzheimer's disease was compared with brain tissue from a placebo group of patients who had not had any symptoms of dementia when they died. Scientists discovered the amount of tau present in the brain was correlated with USP11 levels, and was higher in women than in men. The levels of USP11 were up to 9.5 times higher in people who had been diagnosed with Alzheimer's disease. In mouse models a similar pattern was observed, furthermore, knocking out one X chromosome in female mice resulted in an increase in spatial memory.

'In terms of implications, the good news is that USP11 is an enzyme, and enzymes can traditionally be inhibited pharmacologically,' Dr Kang explained. 'Our hope is to develop a medicine that works in this way, in order to protect women from the higher risk of developing Alzheimer's disease.'

'This study sets a framework for identifying other X-linked factors that could confer increased susceptibility to tauopathy in women,' Dr Kang said.

Genetic mechanisms such as this would not be picked up by genome-wide associated studies as the increased risk is not posed by a variant, but rather the increased expression of a gene in women.