USC Scientists Uncover Hidden Alzheimer's Trigger — And a Drug That May Stop It
USC researchers have pinpointed a key enzyme driving Alzheimer's-linked brain inflammation, along with experimental compounds that could shut it down.
USC Scientists Identify a Hidden Driver of Alzheimer's Disease
Researchers at the University of Southern California have made a significant breakthrough in the fight against Alzheimer's disease, discovering experimental drug compounds that may help curb the dangerous brain inflammation tied to one of the condition's most powerful genetic risk factors.
The findings, published in the prestigious Nature journal npj Drug Discovery, center on an enzyme known as calcium-dependent phospholipase A2 — or cPLA2 — which appears to play a central role in fueling inflammation inside the brain.
The APOE4 Connection
The USC research team first connected elevated cPLA2 activity to Alzheimer's risk while examining individuals who carry the APOE4 gene — the single strongest genetic risk factor currently known for the disease. Not every APOE4 carrier will develop Alzheimer's, but scientists observed that those with heightened cPLA2 activity faced a considerably greater likelihood of doing so.
This discovery opened a compelling new avenue: if cPLA2 is helping drive harmful neuroinflammation in high-risk individuals, could selectively dialing down its activity reduce that risk?
The Challenge: Targeting the Enzyme Without Disrupting Normal Brain Function
The scientific challenge wasn't simple. Since cPLA2 also performs essential roles in healthy brain activity, completely blocking the enzyme wasn't an option. Researchers needed compounds capable of selectively reducing its harmful inflammatory activity while leaving its normal functions largely intact.
Adding to the complexity, any viable drug compound would need to be small enough to cross the blood-brain barrier — a highly selective biological filter that blocks many substances from reaching the brain.
What the Lead Researcher Said
"In this study, we identified compounds that act selectively on cPLA2, with minimal effects on related PLA2 enzymes that are important for normal cellular function," said senior author Hussein Yassine, director of the Center for Personalized Brain Health at the Keck School of Medicine of USC. "Across cell-based and animal models, cPLA2 activity was reduced at low concentrations, indicating that the compounds are potent in brain-relevant systems."
Screening Billions of Molecules to Find the Right Candidate
To identify viable drug candidates, the team deployed large-scale computational screening — a process that evaluated billions of potential molecules. The goal was to zero in on compounds predicted to selectively inhibit cPLA2, successfully penetrate the brain, and remain effective under realistic biological conditions.
This advanced screening methodology was developed by Vsevolod "Seva" Katritch of the USC Dornsife College of Letters, Arts and Sciences and the USC Michelson Center for Convergent Bioscience.
Following the initial screening phase, pharmacologist Stan Louie of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences spearheaded efforts to prepare shortlisted compounds for animal testing and evaluate how efficiently they reached the brain.
Promising Early Results in Lab and Animal Models
One cPLA2 inhibitor rose to the top of the candidate list after demonstrating the ability to reduce harmful enzyme activation in human brain cells exposed to Alzheimer's-related stress conditions.
In subsequent mouse studies, the compound successfully crossed the blood-brain barrier and positively influenced neuroinflammatory pathways associated with Alzheimer's progression — a result that researchers describe as highly encouraging for the treatment of neurodegenerative disorders.
What Comes Next
"Our goal is to find out whether targeting inflammation can alter Alzheimer's risk — particularly in APOE4 carriers," Yassine said. "This next phase focuses not on promises, but on carefully determining whether modulating this pathway is safe, feasible, and ultimately meaningful for human disease."
The study was co-led by Anastasiia V. Sadybekov, Marlon Vincent Duro, and Shaowei Wang, alongside additional contributors from across USC's research divisions.
Funding for the research was provided by the National Institute on Aging, the National Institute of General Medical Sciences, the Department of Defense, the Alzheimer's Drug Discovery Foundation, and several private donors.
Disclosure: Yassine, Katritch, and Louie are founders of PeBRx, a company currently developing cPLA2 inhibitors.
