Gene Therapy Shows Promise for Preventing and Treating Alzheimer's

Scientists at the University of Bristol have developed a gene switch therapy that could potentially prevent and treat Alzheimer's disease. The research, detailed in preliminary findings, involved converting the APOE4 gene, a significant genetic risk factor for Alzheimer's, into the lower-risk APOE3 gene within human cells.

This innovative technique could one day be delivered through a single injection. Alzheimer's disease is the most common form of dementia, accounting for approximately 60% of dementia cases in the UK. While the exact cause of the condition remains unknown, genetic factors play a substantial role in an individual's risk.

The APOE gene provides instructions for a protein that helps transport fats and other substances in the body. Everyone inherits two copies of this gene, one from each parent. The APOE3 variant is the most common and is associated with normal protein function. However, roughly a quarter of the population carries at least one copy of the APOE4 gene, which is linked to an increased risk of developing Alzheimer's. It is believed that the protein produced by APOE4 may be toxic to the brain. Approximately one in 50 people have two copies of the APOE4 gene.

Carrying APOE4 genes does not guarantee the development of Alzheimer's, and lifestyle factors such as physical activity and social engagement can offer protection. Nevertheless, individuals with a single APOE4 variant face double the risk of developing Alzheimer's compared to the average person, while those with two copies face a tenfold increase in risk. The APOE4 gene has also been associated with an earlier and more severe diagnosis.

Dr. Kevin Kemp, a neuroscientist at the University of Bristol and lead author of the study, explained that the APOE4 and APOE3 genes are nearly identical, differing by only a single letter in their genetic code. This subtle difference, however, significantly impacts the APOE protein's function in brain cells. The protein plays a crucial role in maintaining cell health and clearing toxic proteins like amyloid beta, which is strongly implicated in Alzheimer's disease.

The research team utilized a technique that chemically alters a specific part of the genetic code. This process leverages the cell's natural repair mechanisms to make the change permanent. In their experiments, they successfully converted APOE4 to APOE3 in immune cells derived from Alzheimer's patients. A modified virus was used as a delivery system for the genetic code into these immune cells. The study found minimal unintended alterations to the cells' broader DNA.

"The idea is that these immune cells enter the brain and release the lower-risk APOE3 protein," explained Kemp. This protein would then be absorbed by nerve cells and other brain cells involved in Alzheimer's progression, counteracting the harmful effects of APOE4.

Although the findings have not yet been published in a peer-reviewed journal, the team is preparing to submit them for publication. They aspire for this approach to evolve into a therapy delivered via a one-time bloodstream injection. Theoretically, this treatment could be administered to individuals already experiencing Alzheimer's symptoms or used preventatively in those identified as carriers of the APOE4 gene.

Kemp expressed hope for initiating clinical trials in human patients within five to ten years. A significant challenge, however, is the limited availability of genetic testing for APOE4 on the NHS, which is typically reserved for specific cases, such as individuals with a pronounced family history of dementia. Many people are only aware of their APOE4 status through private testing or participation in research studies.

Katharina Cosker, research programmes manager at Alzheimer's Research UK, commented that this research reflects a broader movement to address the fundamental biology of Alzheimer's, coinciding with the emergence of the first disease-modifying treatments and a promising pipeline of new therapies. She noted that new approaches targeting genetic risk factors could expand treatment options, particularly for those for whom current therapies are not suitable, including individuals with two copies of the APOE4 gene.

Dr. Richard Oakley, associate director of research and innovation at Alzheimer's Society, described the early-stage research as an "exciting glimpse" into the future of Alzheimer's treatment. He cautioned, however, that significant progress is still needed, as this was laboratory research on cells and its safety and efficacy in humans remain unknown. Oakley emphasized the urgent need for more effective treatments to slow, stop, or prevent dementia, which affects approximately one million people in the UK.