Liqin Zhao, KU associate professor of pharmacology & toxicology and investigator at the Life Span Institute, has researched the human ApoE gene for years. A major focus of her work centers on how the ApoE2 variant — one of three major isoforms of ApoE gene — might protect people from Alzheimer’s disease.

Now, based upon a discovery made during her Alzheimer’s-disease work, Zhao is patenting a way to leverage rhApoE2 to regulate blood lipids. Lipids, like fats and oils, are building materials of life at the cellular level that also are tied to heart disease and other metabolic diseases.

“In essence, we found that rhApoE2 significantly lowered blood levels of a number of ceramides,” Zhao said. “Moreover, rhApoE2 increased blood levels of a variety of ‘good triglycerides’ — triglycerides that contain health-promoting, long-chain polyunsaturated fatty acids such as alpha-linolenic acid, EPA and DHA, and lowered levels of ‘bad triglycerides,’ or triglycerides that contain saturated or monosaturated fatty acids that can impose a cardiovascular risk.”

More and more, ceramide levels in the blood are seen by medical researchers and clinicians as a promising predictor of heart disease, perhaps a more useful metric than cholesterol readings. For example, the Mayo Clinic recently started using a blood test to quantify plasma ceramides as a new biomarker of cardiovascular risk prediction.

During a two-month experiment, Zhao and her team treated mice genetically altered to have aged vascular and neurological symptoms. They treated mice intravenously with rhApoE2, collected serum samples and then blindly evaluated them with a lipidomics analysis using advanced mass-spectrometry.

“The results were completely unexpected,” Zhao said. “The lipidomics study was meant to determine whether a two-month intravenous exposure to rhApoE2 would cause any type of lipid dyshomeostasis (disruption of biological balance). We were pleasantly surprised to see that rhApoE2 not only did not induce a hyperlipidemic risk profile, but the treatment significantly improved the circulating lipidome of aged ApoE4 mice.”

Zhao said the effect of rhApoE2 is unique, surpassing treatments available currently to patients at risk of heart disease.

“Currently no drugs have the capacity to systematically alter the circulating lipidome like what rhApoE2 has shown us,” she said. “It’s very exciting to envision that rhApoE2 may have the potential to fundamentally transform the treatment of metabolic diseases. In future studies, we’ll need to address what might be the underlying biological basis that led to these effects from rhApoE2. It’s probable that unknown factors, in addition to low-density lipoprotein receptors, may be involved in the dynamic regulation of the metabolism of those lipid classes.”

The promise of ApoE2 as a treatment for human health goes beyond regulating levels of lipids in the blood. Zhao and her team filed a separate provisional patent application last November based on use of rhApoE2 to prevent and treat Alzheimer’s disease.

“Over the last several years, we’ve learned a lot about ApoE2,” the KU researcher said. “As a relatively rare variant, ApoE2 is an extraordinary protein with extraordinary properties. Our hope is that we can identify and translate some of the health benefits ApoE2 can provide into therapeutics for treating human diseases. I think we are in a great place towards accomplishing this goal.”

However, researchers called for more study into whether pharmacy interventions, including patient navigation and more frequent social determinant screenings, would have a greater benefit to certain patients or in specific healthcare settings.

For the study, participants receiving primary care were assigned to receive interventions from pharmacy liaisons dually trained as patient navigators who screened patients for health related social needs every 3 months and connected patients with community resources. The study showed no difference in inpatient hospital admissions and emergency department visits at 12 months, relative to patients who received usual care that included screening for health related social needs every 6 months and a pharmacy liaison focused on medication adherence.

Patients in low-resource communities served by Medicaid Accountable Care Organizations struggle with a number of health-related social needs, such as food insecurity, housing insecurity, and lack of transportation to medical appointments. Patients with unmet health-related social needs are at high risk for preventable healthcare use and high levels of medical expenditure and may prioritize social needs over medical care, which may lead to preventable utilization.

“Given that the majority of study participants identified as members of a racial or ethnic group bearing a disproportionate burden of inequities in health care, it is unsurprising that a health system–based intervention did not improve outcomes,” said Pablo Buitron de la Vega, MD, MSc, general internist and preventive medicine physician at Boston Medical Center and Assistant Professor of Medicine at Boston University Chobanian & Avedisian School of Medicine. “There needs to be interventions outside of the healthcare setting. Policies to reduce income inequality would be more likely to improve health outcomes.”

The non-randomized clinical trial had 364 adult participants and was conducted between May 1, 2019 and March 4, 2021 with one year follow-up. Researchers are not aware of prior trials that have embedded a health-related social needs screening-and-referral intervention or patient navigator in a pharmacy care program to reduce health care usage.