Gene switch therapy could prevent AND treat Alzheimer's

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Gene therapy could be the next breakthrough in preventing and treating Alzheimer's disease in those at risk.

Researchers at the University of Bristol recently reported that they were able to convert the high-risk Alzheimer's gene, APOE4, into the lower-risk APOE3 gene in human cells using a special technology which could one day be delivered by a one-off injection.

Alzheimer's disease is the most common form of dementia, accounting for about 60 per cent of the UK's one million cases.

Scientists have yet to uncover the cause of the condition, but they know that certain factors increase people's risk, including their genetic make-up.

The greatest genetic risk factor relates to which type of APOE gene someone has. The gene provides instructions for making a protein that packages and moves substances such as fats around the body. 

We all have two copies of that gene, one from each parent. The most common variant, which leads to 'normal' protein function, is called APOE3.

However, about one in four of us has at least one copy of the APOE4 gene, which comes with a higher risk of developing Alzheimer's (research last year suggested this is because the protein it creates could be toxic to the brain). About one in 50 of us has two copies of APOE4.

Having APOE4 genes is not a guarantee that someone will develop Alzheimer's and factors such as keeping physically active and staying socially connected are protective against it. 

Scientists have yet to uncover the cause of Alzheimer's, but they know that certain factors increase people's risk, including their genetic make-up and the high-risk gene, APOE4

Researchers at the University of Bristol recently reported that they were able to convert the high-risk Alzheimer's gene, APOE4, into the lower-risk APOE3 gene in human cells (file photo)

But broadly speaking, people with a single APOE4 variant are at double the risk of developing Alzheimer's, while those with two copies are about ten times more likely (compared to the average). The gene also appears to raise the risk of an earlier or more severe diagnosis.

The APOE4 and APOE3 genes are 'extremely similar', explains Dr Kevin Kemp, a neuroscientist and associate professor at the University of Bristol, who led the new study. 'The difference is just one letter in the genetic code of the genes. It is a tiny, tiny difference.'

But this difference means that the protein produced by the APOE gene in brain cells is different and that protein plays a critical role in maintaining cell health and helping to clear toxic proteins such as amyloid beta, which is strongly linked to Alzheimer's, he says.

Using a technique that can chemically alter a specific part in the genetic code and harness the cell's own repair machinery to make the change permanent, the team converted APOE4 to APOE3 in immune cells derived from Alzheimer's patients.

A modified virus acts as a delivery vehicle for the new genetic code into the immune cells. The team checked for any unwanted changes to the cells' wider DNA arising from the experiment and found very little impact.

'The idea is that these immune cells enter the brain and release the lower-risk APOE3 protein,' explains Kevin Kemp. That protein would then be taken up by nerve cells and other cells involved in the progression of Alzheimer's to counteract the harmful effects of APOE4, he says.

The results have not yet been published in a journal, but Kevin Kemp says he plans to do so at a later stage. The team hopes that the approach will eventually lead to a therapy that can be injected into the bloodstream as a one-off treatment.

It could, theoretically, be used for people showing symptoms of Alzheimer's, or as a preventative tool in those identified as having the APOE4 gene, says Kevin Kemp. He is hoping for a clinical trial in patients within five to ten years.

An obvious hurdle is that genetic testing for APOE4 is only available on the NHS in a very small number of cases, such as for people with specific family histories of dementia. So patients only know if they have the gene if they have paid for a private test or are taking part in research.

'This type of research reflects a growing effort to tackle the underlying biology of Alzheimer's at a time when the field is entering a new era, with the first disease- modifying treatments becoming available and a pipeline of new therapies in development,' says Katharina Cosker, research programmes manager at Alzheimer's Research UK. 

'With some current treatments not suitable for everyone, including people who carry two copies of APOE4, exploring new approaches that target genetic risk factors could help expand treatment options.'

Dr Richard Oakley, associate director of research and innovation at Alzheimer's Society, said: 'This early-stage research is an exciting glimpse of what the future of Alzheimer's treatment could look like.

'It's an encouraging first step but there is a long way to go. This was laboratory research in cells so we don't yet know whether it will be safe or effective in the human body.

'With around one million people in the UK living with dementia, we urgently need treatments that can slow it more effectively, stop it progressing or prevent it altogether.'