New therapies for Alzheimer’s disease should target a particular gene linked to the condition, according to researchers who said most cases would never arise if its harmful effects were neutralised.
The call to action follows the arrival of the first wave of drugs that aim to treat Alzheimer’s patients by removing toxic proteins from the brain. While the drugs slow the disease down, the benefits are minor, and they have been rejected for widespread use by the UK’s National Institute for Health and Care Excellence (Nice).
In searching for alternative therapies, scientists at UCL say drug developers should focus on two risk-raising variants of a gene named Apoe. Therapies designed to block the variants’ impact have “vast potential” for preventing the disease, they claim.
Dr Dylan Williams, a genetic epidemiologist at UCL, said: “Most Alzheimer’s disease cases would not arise without the contribution of just this single gene: Apoe. We need to think about it as a direct target. Almost all potential Alzheimer’s cases could benefit from Apoe-related interventions.”
More than half a million people in the UK, and more than 40 million worldwide, are living with Alzheimer’s disease, the most common form of dementia. Several genes contribute to Alzheimer’s risk and lifestyle is important too: smoking, obesity, diabetes, high blood pressure and cholesterol all make the disease more likely.
Williams and his colleagues analysed medical records from more than 450,000 people of European ancestry to calculate how much Alzheimer’s disease arose due to different variants of the Apoe gene. People inherit two copies of the gene – one from each parent – and there are three main variants: Apoe2, 3 and 4.
Scientists have long known that people with two copies of Apoe4 are high risk for Alzheimer’s, though 40% to 70% never develop the disease. The Apoe3 variant is widely considered neutral and the rare Apoe2 variant is regarded as protective.
But Williams said we should see it another way. Compared with carrying two copies of Apoe2, both Apoe3 and Apoe4 raise the risk of Alzheimer’s, he said. Writing in the journal npj Dementia, the team calculate that without these variants, 72% to 93% of Alzheimer’s cases, and about 45% of all dementia, would not have occurred. “If interventions could eliminate the detrimental effects [of Apoe3 and 4], we could expect to prevent most Alzheimer’s disease and a large proportion of all dementia,” they write.
That is a big if. The Apoe gene is crucial for moving cholesterol and other fats around the body and brain, so knocking it out entirely is likely to cause problems. Future therapies might edit the gene variants, or dampen down their activity, but those are neither imminent nor risk-free.
Another problem is that the vast majority of people – more than 99% in the study – carry Apoe3 or Apoe4. So preventing Alzheimer’s would mean treating nearly the entire population, possibly through invasive gene editing of the brain.
The study received a mixed reception. Tim Frayling, professor of human genetics at the University of Geneva, said claiming more than 90% of Alzheimer’s would not occur without the Apoe gene’s effects was like saying more than 90% of road traffic deaths would not occur without the contribution of cars. “People should not worry if they have the risk versions of the gene, because 99.4% of us do,” he said.
But Tara Spires-Jones, professor of neurodegeneration at the University of Edinburgh, said understanding the risk factors that made the brain vulnerable to Alzheimer’s was “essential for developing effective treatments and prevention strategies”, adding that Apoe was one of the most important genetic risk factors.
Dr Sheona Scales, of Alzheimer’s Research UK, said: “Evidence around Apoe3 contributing to Alzheimer’s and dementia risk is significant, as this has been largely thought of as having a neutral effect on risk. However, it’s important to note that not everyone with these Apoe gene variations will go on to develop dementia, as other risk factors also have an influence.
“This research raises lots of interesting questions, such as how Apoe3 and Apoe4 could drive Alzheimer’s risk, their effects in people of non-European ancestry, and whether targeting these variants could be a promising avenue for treatment and prevention of Alzheimer’s.
“Because of the complexity of Alzheimer’s risk, Apoe testing is not available on the NHS for people worried about their risk of developing Alzheimer’s in the future. If you are worried about your dementia risk, you should speak to your GP.”
