New therapies for Alzheimer’s disease should focus on a specific gene linked to the condition, researchers say. They believe most cases coudl be prevented if the harmful effects of this gene were neutralized.
This call for new approaches comes after the first drugs designed to treat Alzheimer’s by removing toxic proteins from the brain have arrived. However, these drugs offer only small benefits and have been rejected for widespread use in the UK by the National Institute for Health and Care Excellence (Nice).
Scientists at UCL suggest drug developers should concentrate on two versions of a gene called Apoe that increase risk. They claim therapies to block the impact of these versions have “vast potential” for preventing the disease.
Dr. Dylan Williams, a genetic epidemiologist at UCL, said, “Most Alzheimer’s disease cases wouldn’t happen without this single gene: Apoe. We need to target it directly. almost everyone at risk of Alzheimer’s could benefit from interventions related to Apoe.”
More than half a million people in the UK,and over 40 million worldwide,live with Alzheimer’s disease,the most common form of dementia. Several genes and lifestyle factors contribute to risk, including smoking, obesity, diabetes, high blood pressure, and cholesterol.
Williams and his team analyzed medical records from over 450,000 people of European ancestry to determine how much Alzheimer’s disease was linked to diffrent versions of the Apoe gene. People inherit two copies of the gene – one from each parent – and there are three main versions: Apoe2,3,and 4.
Scientists have known for some time that people with two copies of Apoe4 are at high risk for Alzheimer’s, even though 40% to 70% don’t actually develop the disease. The Apoe3 version is usually considered neutral, and the rare Apoe2 version is thought to be protective.
However, williams argues for a different view. Compared to carrying two copies of Apoe2, both Apoe3 and Apoe4 increase the risk of Alzheimer’s. The team, writing in the journal npj Dementia, calculated that without these versions, 72% to 93% of Alzheimer’s cases, and about 45% of all dementia, wouldn’t occur. “If we could eliminate the harmful effects of Apoe3 and 4,we could prevent most Alzheimer’s disease and a large portion of all dementia,” they write.
However, this is a meaningful challenge. The Apoe gene is vital for moving cholesterol and fats around the body and brain, so wholly removing it could cause problems. Future therapies might edit the gene versions or reduce their activity, but these are not available yet and carry risks.
Another issue is that most people – over 99% in the study – carry Apoe3 or Apoe4. Preventing Alzheimer’s would therefore mean treating nearly everyone, possibly with invasive gene editing of the brain.
The study received varied reactions. Tim Frayling,professor of human genetics at the University of Geneva,said claiming over 90% of Alzheimer’s wouldn’t occur without the Apoe gene’s effects was like saying most road deaths wouldn’t happen without cars. “People shouldn’t worry if they have the risk versions of the gene, because 99.4% of us do,” he said.
Tara Spires-Jones, professor of neurodegeneration at the University of Edinburgh, said understanding the risk factors that make the brain vulnerable to Alzheimer’s is “essential for developing effective treatments and prevention strategies,” adding that Apoe is a key genetic risk factor.
Dr. Sheona scales, of Alzheimer’s Research UK, said, “Evidence around Apoe3 contributing to Alzheimer’s and dementia risk is significant, as it has frequently enough been thought to have a neutral effect. Though, it’s vital to remember that not everyone with these Apoe gene variations will develop dementia, as other risk factors also play a role.
“This research raises critically important questions, such as how Apoe3 and Apoe4 drive Alzheimer’s risk, their effects in people of different backgrounds, and whether targeting these versions could be a promising treatment and prevention strategy.
“Because Alzheimer’s risk is complex, Apoe testing isn’t available on the NHS for people worried about developing the disease. If you’re concerned about your dementia risk, talk to your doctor.”
