By studying the APOE4 gene and its impact on brain inflammation and metabolism of fatty acids, Keck School of Medicine of USC researcher discovers potential new ways to prevent cognitive decline

By Hope Hamashige

(photo USC)

For decades, the thinking about Alzheimer’s disease has been dominated by the so-called amyloid hypothesis which proposes that an abnormal accumulation of amyloid-beta plaques in various parts of the brain is the main driver of a cascade of events, leading to the loss of synapses and the death of neurons causing deficits in cognition and memory.

But as the search for an effective treatment continues, some scientists have begun exploring new ways of thinking about Alzheimer’s disease in the hope of finding new, more promising ways to prevent and treat this and other types of dementia.

PET image of the brain of an APOE4 target replacement mouse model injected with a radioactive arachidonic acid tracer developed with Kai Chen, PhD/USC Radiology. Red areas show arachidonic acid, a type of fatty acid. The Yassine Lab uses this technology to study how APOE4 affects brain lipids and inflammation. (Photo Marlon Vincent Duro, PhD)

One such researcher is Hussein Yassine, MD, an endocrinologist who treats patients with diabetes and lipid disorders. Lipids are organic compounds that are insoluble in water, such as fats and oils, and they serve different functions in the body. He is studying the role lipids in the brain may play in brain health.

“There is significant reason to believe it is not only the buildup of amyloid and that there are many other ways people can develop Alzheimer’s disease and other types of dementia,” said Hussein Yassine, MD, associate professor of medicine and neurology at the Keck School of Medicine of USC. “The system that keeps the brain healthy is complex and there are several ways that it can fail.”

The APOE4 gene and its link to system failures in the brain

Yassine has spent the past decade studying the role of a specific variant of the apolipoprotein E (APOE) gene, which is involved in lipid metabolism. APOE is a protein that makes lipids soluble in the blood and carries lipids in the body as high-density lipoprotein (HDL).

The variant, called APOE4, is a known risk factor for developing Alzheimer’s and is present in up to 50% of all people with Alzheimer’s dementia. The APOE gene has numerous roles in the brain and APOE4 is connected to several different types of system failure, all of which can put a person at risk of developing Alzheimer’s disease.

“In APOE4 carriers, it seems that when the system is stressed, a number of things can go wrong. The blood vessels can become leaky, inflammation can persist longer, the brain might not be getting the energy it needs from the rest of the body,” said Yassine. “APOE4 is also associated with low grade inflammatory processes within the brain, which was once believed to be a result of Alzheimer’s disease but is now recognized to be one of the drivers. There are many ways the system can get hit and we don’t think it is just one thing that can lead to Alzheimer’s. Some people with APOE4 may never get this disease, but with more hits, the system in APOE4 carriers starts to fail.”

APOE4’s impact on fatty acids in the brain

APOE4 also affects how fats and other nutrients, which are essential for proper maintenance of the brain, are delivered to the brain. It has been shown that APOE4, for example, can lead to break down of fatty acids, such as omega-3, which may explain why APOE4 carriers with Alzheimer’s lack certain omega-3 fatty acids in the brain and may not respond to supplementation once dementia develops. By understanding the variety of ways APOE4 may initiate the process of system failures in the brain, Yassine hopes to discover ways to intervene long before neurons die, preventing the development of Alzheimer’s and other dementias.

“We want to understand how APOE4 changes the brain from age 20 to 80 because a lot is happening in midlife that affects the aging brain,” said Yassine. “By the time people develop symptoms, it is too late for intervention, so we need to know what changes are taking place long before neurons begin to die.”

One focus of Yassine’s lab is understanding the mechanisms behind faulty lipid metabolism and neuroinflammation, in the hopes of identifying new treatment targets to prevent the development of Alzheimer’s. Yassine’s lab recently identified a protein known as cPLA2, which is involved in the development of neuroinflammation, that is activated in brains of APOE4 carriers who developed dementia.

The search for new treatments

Yassine’s team is collaborating with colleagues at the USC School of Pharmacy, and the Departments of Quantitative and Computational Biology and Chemistry at USC Dornsife College of Letters, Arts and Sciences to find drugs that might inhibit cPLA2. An effective cPLA2 inhibitor could be a potential treatment to curb neuroinflammation and improve the brain uptake of fatty acids in APOE4 carriers.

They have also launched a clinical trial, called PREVENTE4, to test whether giving people with APOE4 high doses of omega-3 fatty acid supplements can prevent or curtail cognitive decline before Alzheimer’s disease develops.

It has been proven that APOE4 oxidizes omega-3s and that low levels of the long-chain omega-3 fatty acids DHA and EPA increase the risk of Alzheimer’s disease. In earlier studies, Yassine’s team found that cognitively healthy participants who took omega-3 supplements had 200 percent more DHA in their blood compared to the control group and 28 percent more in the cerebrospinal fluid, a measure of brain uptake. However, APOE4 carriers had lower increases in brain DHA and EPA than non-carriers after supplementation.

In addition, Yassine is studying HDL particles, the so-called good cholesterol, which doctors routinely test for in patients’ blood, but not in the brain. Yassine’s team helped develop an assay to measure HDL in the brain and found that it correlates with cognitive function. They have since identified a protein that increases HDL in blood and are trying to figure out if reengineering this protein can lead to a new treatment to increase the formation of brain HDL.

Yassine also combines his expertise as an endocrinologist with his interest in Alzheimer’s disease to explore the connection between diabetes and Alzheimer’s disease. Most recently, he published a review on the utilization of a class of diabetes drugs known as glucagon-like peptide 1 receptor agonists, which, appear to have significant neuroprotective effects and are being evaluated as treatments for Alzheimer’s disease.

Yassine is starting a clinic for dementia prevention in the Department of Neurology at the Keck School that will focus on APOE4 carriers and others at high risk for dementia. Yassine will use his clinical background in endocrinology and nutrition to help patients with personalized recommendations on diet, lifestyle, lipids, blood pressure, and sugar control with the goal of promoting vascular health and brain health.

Ultimately, he hopes to create a Center for Personalized Brain Health with distinct expertise in APOE4 research, training and education and clinical trials. The center would also provide carriers of APOE4 with personalized, tailored clinical care through the course of their adult lives that could potentially help prevent Alzheimer’s disease.

“There is a lot more research that needs to be done, but we are making tremendous progress,” said Yassine. “There is definitely reason to be hopeful. And the more research we do, the more we are going to be able to develop new treatments to help APOE4 carriers avoid developing this devastating disease.”