In partnership with the Alzheimer Disease Research Center of USC, Hussein Yassine, MD, assistant professor of medicine at the Keck School of Medicine of USC, was awarded two National Institutes of Health R01 grants totaling $6.7 million to conduct research that aims to further the medical community’s understanding of a genotype present in people with heightened risk of Alzheimer’s disease.

Yassine and his team will study how lipid metabolism varies by apolipoprotein (APOE) genotype in persons at risk for Alzheimer’s disease. The APOE4 gene is a strong risk factor for Alzheimer’s disease but how it is involved in Alzheimer’s remains a mystery, Yassine said.

Clues to this mystery may lie in the understanding of the basic biology of the protein that is produced from APOE4, he said, explaining that the protein normally carries important lipids such as omega-3 fatty acids from the bloodstream to the brain. In the brain, these fatty acids such as docosahexaenoic acid, or DHA, are critical for memory functions.

“One in five people carry at least one copy of the gene variant but we still don’t know how it is involved in Alzheimer’s disease,” Yassine said. “In our first project we are looking at using high dose omega-3 supplements for prevention rather than treatment, while in our second project we are studying the function of APOE4 in the brain.”

In the first project, the team hopes to obtain information to help tailor omega-3 supplementation in people who carry the APOE4 gene to help prevent or delay the onset of Alzheimer’s disease.

“We believe that DHA may be a protective factor against Alzheimer’s disease but that it does not penetrate into the brain well enough in persons carrying the APOE4 gene,” Yassine said. “We have given omega-3 to people with Alzheimer’s but it doesn’t work because once your brain cells die, it’s too late. So we turned it around to see if we could use omega-3 for prevention in people at heightened risk based on APOE genotype.”

In the second project, Yassine will measure the functional activity of APOE in cerebrospinal fluid (CSF) among persons with and without the APOE4 gene. This project will monitor associations between Type-2 diabetes and CSF amyloid, tau and cognitive decline for five years.

The USC team includes Helena Chui, MD, chair and professor of neurology; Lon Schneider, MD, MS, professor of psychiatry and the behavioral sciences; Wendy Mack, PhD, professor of preventive medicine; Meredith Braskie, PhD, assistant professor of research neurology; Duke Han, PhD, associate professor of family medicine (clinical scholar); Meng Law, MD, professor of radiology; and Paul Thompson, PhD, professor of ophthalmology, neurology, psychiatry and the behavioral sciences, radiology and engineering.  Collaborators from Pasadena’s Huntington Medical Research Institute include Michael Harrington, MB, ChB, and Alfred Fonteh, PhD.