Hussein Yassine | A fresh approach to Alzheimer’s prevention

Endocrinologist Hussein Yassine’s, MD, own ambitious drive to prevent Alzheimer’s disease began with a mystery.

It turns out that the strongest genetic risk factor for Alzheimer’s disease is a variant called APOE ε4, carried by about half of disease patients. Having two copies of the variant can multiply risk by as much as 12 times, as that spot in the genome codes for a protein that plays an important role in transporting cholesterol. How the APOE gene and the ε4 variant relate to the brain had been poorly understood in the past.

Studying cholesterol — and particularly the high-density lipoprotein (HDL) commonly called “good cholesterol” — has been an area of expertise for Yassine. The key connection between Alzheimer’s and the science of lipids was provided by his mentor and friend Helena Chui, MD, USC’s Raymond and Betty McCarron Chair in Neurology, who approached Yassine back in 2013.

“She told me, ‘As neurologists, we don’t know enough about what APOE ε4 does and how it functions,’” Yassine said. “‘Given that you study apoE proteins in blood, would you be interested in looking at what it does in the brain?’ I told her I’d give it a shot.”

Embracing that challenge led to a series of discoveries. By using cerebrospinal fluid samples from the Alzheimer’s Disease Research Center at USC, Yassine is drawing the link between APOE ε4 and Alzheimer’s into focus. The team found a protective association between small HDL particles in CSF and less Alzheimer’s pathology.

“We think there is a real chance to push back this disease if we can start intervening 20 years before it manifests. We’re going to provide personalized interventions while patients are asymptomatic, with a high promise that they’ll benefit later on.”

Hussein Yassine

Clues that small HDL plays a protective role in neurological health have led to a drug discovery program with one agent, a peptide, designed to increase brain small HDL that is now moving into clinical trials. The Yassine Lab is also looking at mechanisms of brain inflammation. Collaborating with experts across disciplines such as USC computational biologists and pharmacists, Yassine and collaborators discovered a new compound with possible protective effects that blocks an enzyme known as cPLA2, overactivated in APOE ε4 carriers, that breaks down omega-3 fatty acids and drives inflammation in the brain.

Venturing into relatively unknown areas of research, he emphasizes diligence and rigor.

His research trainees conduct numerous experiments using different lab models to confirm that the group is zeroing in on the right biochemical signal. In developing the enzyme-blocker, the researchers have screened billions of molecules and repeatedly refined candidates. The upside is a current compound that is 100 times more potent than what they found at first.

“There’s a huge responsibility before somebody calls their research a breakthrough,” Yassine said. “The biology that we do in the lab, I meet with extreme skepticism. We repeat any preliminary findings to confirm their validity.”

Drug discovery is just one arm of a multipronged program at the USC Center for Personalized Brain Health, which Yassine launched in 2023 as founding director. He and his colleagues interrogate the basic biology of APOE ε4 and Alzheimer’s in search of new markers for the disease. They apply contemporary technology for early detection of problems with brain function that precede telltale memory lapses. They also create new biomedical imaging techniques to identify changes in the brain before midlife that can be used to predict dementia risk as an older adult.

Yassine is particularly excited about the patient-facing side of the Center for Personalized Brain Health. At the recently opened Prevention Clinic at Keck Medicine, patients can obtain genetic testing and evaluations of function in the brain, blood lipids, metabolism and blood vessels. These details lead to tailored guidance for synergistically reducing their individual risks of Alzheimer’s and dementia.

The clinic is the first of its kind in Alzheimer’s care. Already, patients are traveling from as far afield as the East Coast to gain advice for prevention.

“We think there is a real chance to push back this disease if we can start intervening 20 years before it manifests,” Yassine said. “There are certain things that you can do to decrease dementia risk, and we have the opportunity to give the best protocols we have, whether it’s about exercise, diet, sleep, blood pressure, cholesterol or diabetes. We’re going to provide personalized interventions while patients are asymptomatic, with a high promise that they’ll benefit later on.”