The new brain center will focus on research translating genetic, metabolic and molecular insights into interventions that protect those at risk before brain changes set in.

By Wayne Lewis

Image: iStock

The medical community can foresee a looming increase in Alzheimer’s disease, the most common form of dementia, as the population ages. The number of Americans affected is projected to nearly triple by 2050, from 6 million to 16 million. Although a couple of treatments for early disease designed to slow progression have been approved by the Food and Drug Administration, the injury to brain tissue that strikes at memory — and at patients’ very identity — seem irreversible.

Researchers at the Keck School of Medicine of USC are determined to gain a deeper understanding of factors underlying Alzheimer’s and use what they find to intercede, decades before damage sets in. Driving this work is a new interdisciplinary program, the USC Center for Personalized Brain Health.

The starting place for the center’s work is a relatively common genetic variant, called APOE4. The one in four people who carry one copy of the gene are at higher risk for Alzheimer’s. Compared to the general population, the 2 or 3% of people who have two copies face eight to 12 times the risk for the disease. More than half of Alzheimer’s patients have the APOE4 gene.

“USC has a really rich ecosystem … The new center will bring together diverse investigators and providers with a unified vision — a future in which Alzheimer’s disease is no longer a serious threat.”

“Most people with APOE4 don’t get neurological attention until they have dementia,” said endocrinologist Hussein Yassine, MD, director of the Center for Personalized Brain Health and associate professor of neurology, medicine and physiology and neuroscience at the Keck School of Medicine. “Our center is going to provide resources to these individuals well before they get the disease, in hope that this may be the right time to intervene.”

The center’s central projects comprise building a registry of APOE4 carriers, imaging the brain for early detection and intervention, developing interventions (such as diet and exercise) that can be deployed for prevention, profiling Alzheimer’s-related changes that precede clinical symptoms, and developing drugs focused on neuroinflammation once clinical dementia ensues.

“Alzheimer’s disease is one of the biggest challenges we face in human health,” said Carolyn Meltzer, MD, dean of the Keck School, May S. and John H. Hooval, M.D., Dean’s Chair and professor of radiology. “Taking it on calls for research that is both creative and rigorous, backed by enabling resources. That combination makes the Center for Personalized Brain Health an exciting vehicle for the Keck School to ignite lasting change in dementia research and care while advancing precision medicine.”

A connection between basic science and clinical impact for Alzheimer’s disease

Yassine and his colleagues have already uncovered details about the mechanisms behind Alzheimer’s disease and its progression. The Center for Personalized Brain Health will channel these insights into a larger-scale endeavor linking lab findings to clinical care, and vice versa.

According to Yassine, that translational focus fulfills a complementary role alongside existing infrastructure at the Keck School and the university overall: The USC Zilkha Neurogenetic Institute pursues basic discovery, and the USC Mark and Mary Stevens Neuroimaging and Informatics Institute identifies the changes dementia causes in the brain. Meanwhile, there are outstanding resources for clinical research at the USC Alzheimer’s Therapeutic Research Institute and the USC Alzheimer Disease Research Center.

“USC has a really rich ecosystem,” Yassine said. “The new center will bring together diverse investigators and providers with a unified vision — a future in which Alzheimer’s disease is no longer a serious threat.”

Indeed, the Center for Personalized Brain Health’s interdisciplinary efforts will integrate expertise in genetics, neuroscience, neuropsychology, computer science, radiology, pharmacy and nutrition in order to break ground, and provide help, on numerous fronts.

Following the clues from gene to potential Alzheimer’s prevention

APOE4 is a version of a gene that encodes a protein that helps the body transport and make use of certain fats and oils. Exploring the connection between metabolism and brain health drew Yassine to zero in on omega-3 fatty acids and their role in the brain’s self-maintenance system among those with APOE4 decades before the onset of clinical disease.

A 2017 imaging study of APOE4 carriers aged 35 showed that their brains were hungry for omega-3s. That change appears years before damage begins accumulating and decades before the typical onset of Alzheimer’s disease symptoms. In this difference, Yassine saw the potential for prevention and launched the PreventE4 trial to test whether starting omega-3s early in people with APOE4 can slow down disease progression.

Identifying APOE4 carriers showing subtle, early changes in their brain could yield new information about Alzheimer’s progression and — more importantly — inform interventions that lower risk. So Yassine has teamed up with Kai Chen, PhD, associate professor of research radiology at the Keck School, to invent a new imaging technique that traces omega-3s in the brain. Bringing this probe forward from lab studies to human observation will be one major focus of the Center for Personalized Brain Health.

“We’ll be giving personalized advice, and we think that if we can start at 40 — instead of 60 or 65 — we’ll have a better chance at defeating Alzheimer’s disease.”

The center will also maintain a drug development program, with one promising lead currently under investigation. This search started with findings that the APOE4 dementia brain accelerates the breakdown of omega-3s in the brain, such that simply ingesting more doesn’t help.

Aiming to halt the breakdown process itself, Yassine teamed up with Vsevolod Katritch, PhD, associate professor of quantitative and computational biology and chemistry at USC Dornsife College and a member of the USC Michelson Center for Convergent Bioscience, to identify a new compound, called BRI-50054, that reversed omega-3 breakdown in lab studies. Together with Stan Louie, PharmD, professor of clinical pharmacy at the USC Mann School of Pharmacy and Pharmaceutical Sciences, the team is planning to develop BRI-50054 into a drug for Alzheimer’s disease.

The Center for Personalized Brain Health brings together complementary expertise across USC schools to advance this compound and others in a pipeline of candidates for early medical intervention.

“It looks like we have to fix the wiring that’s destroying the omega-3s,” Yassine said, “and take action before it’s too late.”

In a third main element of activities at the Center for Personalized Brain Health, researchers will examine another possible early warning sign for Alzheimer’s disease in those with APOE4.

The same part of the brain that helps people navigate through the world, like internal GPS, is also the primary location stressed by being starved of omega-3 fatty acids. That detail suggests that detecting the deterioration of an APOE4 carrier’s ability to find their way around during middle-age might play into earlier diagnosis of Alzheimer’s. Colleagues at the USC Viterbi School of Engineering and USC Schaeffer Center for Health Policy & Economics are contributing to a forthcoming Center for Personalized Brain Health project using sensors and wearable devices to spot a rise in navigation errors among people with APOE4 around the age of 50.

“There may be digital footprints that can tell us that something is off,” Yassine said. “We want to see if we can capture those changes early and get information that will allow us to intervene.”

Feeding into all the above areas of focus, the Center for Personalized Brain Health aims to build up a cohort of APOE4 carriers age 40 and above in the Los Angeles area.

This effort, dubbed USC GeneScreen, requires the completion of a short questionnaire and the return of a swab for testing to identify those with the gene. Ultimately, the Center for Personalized Brain Health aims to enlist 1,000 people with APOE4 to take part in research and, if they desire, receive personalized care from a dedicated clinic launching in 2024. Depending on factors such as whether a person has one or two copies of the gene, recommendations could include a modified diet, regular exercise and avoiding activities that risk head trauma.

“People should know, if you’ve discovered you are an APOE4 carrier, you will have a place to go,” Yassine said. “We’ll be giving personalized advice, and we think that if we can start at 40 — instead of 60 or 65 — we’ll have a better chance at defeating Alzheimer’s disease.”

To learn more about Hussein Yassine’s research, click here.