Hussman Institute Alzheimer’s Experts Lead APOE4 Research at NIH Meeting
Article Summary
- John P. Hussman Institute for Human Genomics researchers were prominent at the National Institutes of Health meeting to determine next steps in the fight against Alzheimer’s disease.
- The meeting concluded with a consensus to start moving toward human clinical trials on therapy to lower APOE4.
- Meeting time was devoted to the latest findings of genetic ancestries across diverse populations, why APOE4 risk differs among populations and how differences can help us understand the pathobiology of Alzheimer’s.
Led by researchers from the John P. Hussman Institute for Human Genomics at the University of Miami Miller School of Medicine, heavyweights in the race to treat Alzheimer’s disease gathered at the National Institutes of Health (NIH) main campus in Bethesda to determine next steps in the fight.
The two-day meeting, prompted by the identification earlier this year of the APOE4 variant as toxic and a target for therapeutics, concluded September 6 with a consensus to start moving toward human clinical trials on therapy to lower APOE4.
“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. “We all agree we need to do something about Alzheimer’s because an estimated 150 million people will have the disease in 25 years.”
Clinical Trials to Target APOE4
Roughly 1,000 experts in genetics, molecular biology, functional genomics and artificial intelligence/machine learning generated new insights into the effects of APOE on the brain and ways to target this toxic molecule. Drug company representatives interested in developing clinical trials that reduce APOE4 were also in attendance.
“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 Anthony Griswold, Ph.D., associate professor of human genetics and director of bioinformatics at the John P. Hussman Institute for Human Genomics. “It really shows the impact that a genetic finding can have on moving toward therapeutics.”
High-profile participants included former NIH Director Dr. Francis Collins and Dr. Richard Hodes, director of the NIH’s National Institute on Aging (NIA), which sponsored the meeting.
“We established the basics and got everyone up to speed on our area of particular expertise,” said Dr. Vance, who co-organized the meeting and was lead author on the paper published earlier this year in the Annals of Neurology naming the molecule as the best target for therapeutics. “You are born with APOE4, so when do you need to interfere and start therapy? How often do you need to give therapy? It’s not a straightforward thing. But everyone is excited about the opportunity because amyloid antibody therapy has not been as successful as everyone had hoped.”
Relevant meeting topics concerned the latest findings of genetic ancestries across diverse populations, why APOE4 risk differs dramatically among populations and how these differences can be leveraged to better understand the pathobiology of Alzheimer’s.
Considering the Hussman Institute has long been an epicenter of Alzheimer’s research and focuses largely on the populations disproportionately impacted by the disease, including Hispanics, African Americans and others of African, Amerindian descent, it makes sense that Miller School scientists were prominent in the conversation.
APOE Genetics Takes Center Stage
The meeting’s opening session was entirely a panel of Hussman Institute experts discussing APOE genetics. In addition to serving as a moderator, Dr. Vance presented his research on the protectiveness of 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 shed light on the differential APOE effects on gene expression in different types of human brain cells. He shared unpublished data generated in his lab 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.
Margaret Pericak-Vance, Ph.D., director of the Hussman Institute and the Dr. John T. Macdonald Foundation Professor of Human Genetics Executive Vice Chair, helped discover the APOE4 effect on late-onset Alzheimer’s disease risk and is leading the DAWN Alzheimer’s Research Study, presented a history of APOE4 study, from discovery to diversity. Farid Rajabli, Ph.D., assistant professor of human genetics at the Miller School, discussed local-versus-global ancestry in APOE.
Most Alzheimer’s drugs on the market target amyloid protein accumulation. These drugs have yielded disappointing results, so APOE4 has resurfaced as a potentially fruitful target, since roughly half of Alzheimer’s patients have at least one copy of the gene. Researchers, led by Dr. Vance, set out to determine whether the increased risk from APOE4 came because it is a toxic molecule or one that lacked normal function.
“We found it was toxic and needs to be therapeutically reduced, and that was a major step forward,” Dr. Vance said.
Plotting a Path Forward
With new leads but more questions than answers, Dr. Vance and Washington University’s David Holtzman, M.D., concluded with a meeting-wide brainstorming session to outline the questions that need to be answered to move ahead with therapy targeting APOE4.
“What are the therapeutic implications of raising and lowering APOE?” Dr. Vance said. “What else needs to be understood about variants in different populations? Where do we go from here?”
Stay tuned. Now that the lead experts tackling this immense health challenge have vowed to chart a path toward human clinical trials. As they continue their research, Dr. Vance and colleagues will be publishing a paper answering these questions and more.
Tags: Alzheimer's disease, APOE4 gene, DAWN Alzheimer's Research Study, Dr. Anthony Griswold, Dr. Farid Rajabli, Dr. Jeffery Vance, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Margaret Pericak-Vance, John P. Hussman Institute for Human Genomics