Breakthrough highlights the role of genes in Alzheimer's

Scientists identify three more genes that increase the risk of getting the most common form of the disease

Scientists have discovered that three known genes play important roles in determining the risk that someone will develop Alzheimer's disease – a finding that could lead to new treatments and a possible early test for one of the most feared disorders of later life.

It is the first time in 15 years that researchers have identified new genetic factors that definitely raise someone's risk of getting the degenerative brain disease.

The breakthrough means that a total of four genes are now known to contribute to Alzheimer's. Scientists hope that further genetic discoveries could soon lead to a diagnostic test that can provide a meaningful assessment of whether someone is likely to develop the condition.

Such a test would help doctors to identify patients at greatest risk of the disease, although it might also be seized upon by insurance companies and other organisations concerned about the cost of long-term healthcare in old age. Alzheimer's disease is one of the fastest growing and most costly medical conditions in the developed world. In Britain, about 700,000 people have some form of dementia including Alzheimer's disease.

This will grow to about 940,000 by 2015, and to more than 1.7 million by 2051, as a result the ageing population.

Two large international teams of researchers announced their findings last night, saying that detailed scans of the entire genomes of a combined total of nearly 20,000 people from eight countries have implicated the three genes, which were already known to play important roles within the brain.

Sir Leszek Borysiewicz, the chief executive of the Medical Research Council (MRC), which part-funded the British study, said the findings, published in the journal Nature Genetics, were crucial in piecing together the complicated picture that can help to explain the Alzheimer's puzzle.

"This study is a huge step towards achieving an earlier diagnosis of Alzheimer's and improving the lives of the many people affected by the disease," Sir Leszek said.

In the British study, carried out at the MRC's Centre for Neuropsychiatric Genetics and Genomics in Cardiff, scientists analysed more than half a million differences in the DNA in each of 4,000 people who had Alzheimer's, and compared them with the DNA of 8,000 people without the disease. A comparable study carried out by the European Alzheimer's Disease Initiative in France compared nearly 4,000 Alzheimer's patients with a comparable number of people who did not have the condition. The British study found two genes and the French found the third, as well as confirming one of the British discoveries.

Professor Julie Williams of Cardiff University, who led one of the research teams, said that the findings are "significant and conclusive" in terms of linking variations in the three genes to the risk of developing Alzheimer's.

"If we were able to remove the detrimental effects of these genes through treatments, we could reduce the proportion of people developing Alzheimer's by 20 per cent," Professor Williams said. "In the UK alone this would prevent just under 100,000 people developing the disease."

The three new genes implicated in Alzheimer's are called CLU, PICALM and CR1. They are the first genes linked to the disease since the discovery 15 years ago of the role of the APOE gene in raising the risk of Alzheimer's.

"Three of the risk genes, APOE, CLU and CR1, have roles in protecting the brain from damage. Perhaps the changes we see in these genes remove this protection or may even turn them into killers," Professor Williams said.

"Our results may highlight new targets for treatments. For example, CLU has a role in dampening down inflammation in the brain," she said.

"Up until now, increased inflammation seen in the brains of Alzheimer's sufferers had been viewed as a secondary effect of disease," she said.

"Our results suggest the possibility that inflammation may be primary to disease development."

Professor Michael Owen, director of the MRC centre said the research will next be expanded it to a full genome-wide analysis of 60,000 volunteers.

This should allow the scientists to pinpoint changes in other genes that play a smaller, yet significant role in raising the risk of Alzheimer's.

The value of this genetic approach to studying Alzheimer's has now been established beyond a doubt, he said.

Alzheimer's: A tangled web

*Alzheimer's disease is a degenerative disorder of the brain and is only truly diagnosed following a post-mortem examination to identify the build-up of protein bundles or tangled "plaques" at the twisted nerve endings of affected brain cells. It is not known whether these tangles or plaques are the cause of all or indeed any of the recognised symptoms of the disease – such as memory loss and cognitive impairment – but they can always be found in the brain of patients who have died of Alzheimer's. It is known that genes play an important role in Alzheimer's. For instance, three genes have been found to explain the rare cases of early-onset Alzheimer's, which is inherited and tends to run in certain families. However, 99 per cent of Alzheimer's patients suffer from the late-onset form of the disease – often called "sporadic" Alzheimer's because it seemingly occurs at random within the population. Nevertheless, it is becoming increasingly clear that even this most common form of the disease has a genetic component, in addition to any environmental factors. Four genes have now been implicated in raising the risk of sporadic, late-onset Alzheimer's. Four variations of the APOE gene, for instance, were identified as a risk factor 15 years ago. Now, three more genes have been added to the list – CLU, PICALM and CR1. It is not yet possible for scientists to give accurate assessments of how much risk each of these genes – or more accurately the variations in the genes – add to a person's chances of getting the disease. However if the effects of the three latest genes were removed from the population as a whole,then something like 100,000 people in Britain alone may be prevented from getting Alzheimer's. Anything that increases our understanding of this debilitating disease, which often results in long-term care, will pay dividends as the population ages significantly in coming decades.

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