It might one day be possible to gene-edit brain cells to prevent Alzheimer鈥檚 disease. Researchers have discovered that altering a key gene in human nerve cells reduces the formation of a protein associated with the disease, though so far this has only been done in a dish.
Alzheimer鈥檚 is the main cause of dementia and the risk rises sharply as we grow old. Around 1 in 4 people aged over 90 have it.
The cause of Alzheimer鈥檚 still isn鈥檛 fully understood, but the leading hypothesis is that a build-up of clumps of a protein called beta-amyloid outside cells is to blame. Beta-amyloid forms when another protein, the amyloid precursor, is cut by an enzyme called beta-secretase.
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In 2012, researchers found that a few people of Scandinavian ancestry have a gene variant called A673T that makes them . 鈥淵ou are not only protected from Alzheimer鈥檚, you have a tendency to live longer,鈥� says Jacques Tremblay at Laval University in Canada. 鈥淭here is no downside.鈥�
Many variants of the gene for the amyloid precursor protein increase the risk of Alzheimer鈥檚. But the A673T variant, which involves a change in a single DNA letter, instead reduces beta-amyloid production by altering the site to which the beta-secretase enzyme binds. It also makes the resulting beta-amyloid less likely to clump together.
The A673T variant is found in roughly 1 in 150 people in Scandinavia, but is rare elsewhere. Because its benefits kick in very late in life, it isn鈥檛 selected for by evolution, says Tremblay, meaning the variant doesn鈥檛 spread.
Engineering the variant into people鈥檚 brain cells could have many of the same benefits as inheriting it, he believes. His team has taken the first step to proving that by showing that beta-amyloid production is reduced when this change is made in human cells growing in a culture dish.
The researchers are still refining the technique before trying it in animals. Tremblay initially used a CRISPR technique called base editing to make the necessary single-letter change in DNA. He has now switched to a method developed just last year. 鈥淭his new technology, called prime editing, is fantastic,鈥� says Tremblay.
But even working with cells in a dish, the team didn鈥檛 manage to alter them all 鈥� just 40 per cent in the latest experiment using prime editing. A higher proportion might be needed, says Selina Wray at University College London, and achieving this in the human brain will be much harder.
Another major problem is that by the time people start to show the symptoms of Alzheimer鈥檚, it might be too late for gene editing to make a difference, says Wray. But this is true for any Alzheimer鈥檚 treatment, and the gene-editing approach is still worth pursuing, she says. 鈥淲e should be considering as many potential therapies as possible.鈥�
For initial clinical trials, Tremblay plans to get around this problem by trying the approach in people with mutations known to cause early-onset Alzheimer鈥檚.
If human germline genome editing does start to be widely used, this change could also be made in sperm, eggs or embryos, so people are born with the A673T variant. 鈥淚n the long term, I think that this will probably happen,鈥� says Tremblay.
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