Researchers at the National Institutes of Health (NIH) have agreed to move forward with human clinical trials targeting the APOE4 variant as a therapeutic strategy for Alzheimer's disease. The decision, reached at a recent NIH meeting, marks a significant step in the development of new treatments for the debilitating condition, which is projected to affect 150 million people in the next 25 years.
The meeting, prompted by the identification of APOE4 as a toxic molecule and potential therapeutic target, brought together approximately 1,000 experts in genetics, molecular biology, and drug development. Participants explored the effects of APOE4 on the brain and strategies to reduce its toxicity.
Clinical Trials to Target APOE4 Toxicity
"We still need to continue research in parallel, but it was felt we know enough to push ahead, as the need is great, especially for those at risk without yet developing symptoms," said Jeffery Vance, M.D., Ph.D., professor in the Dr. John T. Macdonald Foundation Department of Human Genetics at the Miller School. Drug company representatives expressed interest in developing clinical trials focused on reducing APOE4 levels.
Anthony Griswold, Ph.D., associate professor of human genetics and director of bioinformatics at the John P. Hussman Institute for Human Genomics, noted the potential impact of genetic findings on therapeutic development. "It's really exciting to see that companies are investing time and money to have clinical trials with the goal of reducing APOE, which follows from our data that lowering APOE may lower risk for Alzheimer's disease," said Dr. Griswold.
APOE Genetics and Ancestry
Meeting discussions also addressed the varying risk associated with APOE4 across different populations. Researchers are investigating why the APOE4 risk differs dramatically among populations and how these differences can be leveraged to better understand the pathobiology of Alzheimer’s.
Dr. Vance presented research on the protective effects of the PSG haplotype for APOE4. "We are very interested in the difference in risk between the APOE4 gene inherited from African ancestors versus European ancestors," he said. "The risk does vary between populations and our group showed this is due not to the gene itself but to the controlling areas around APOE, which we call local ancestry. We have discovered a protective region about 2 million base pairs away that drops the risk in Africans about 75 percent. So let's look at that further and use it as a tool to try and figure out why that is and maybe we can therapeutically mimic it."
Dr. Griswold shared unpublished data illustrating the negative effects of increased amounts of APOE and the parts of the genome that might be responsible for how much APOE is made.
The DAWN Alzheimer's Research Study
Margaret Pericak-Vance, Ph.D., director of the Hussman Institute, presented a history of APOE4 study, from discovery to diversity and highlighted the DAWN Alzheimer's Research Study. Farid Rajabli, Ph.D., assistant professor of human genetics at the Miller School, discussed local-versus-global ancestry in APOE.
A Shift in Therapeutic Focus
Most Alzheimer’s drugs on the market target amyloid protein accumulation. However, these drugs have shown limited success, leading to renewed interest in APOE4 as a therapeutic target. Roughly half of Alzheimer’s patients have at least one copy of the APOE4 gene.
"We found it was toxic and needs to be therapeutically reduced, and that was a major step forward," Dr. Vance said, emphasizing the importance of targeting APOE4 toxicity.
