Study Aims to Stop Alzheimer’s Inflammation in APOE4 Carriers

Summary: Late-onset Alzheimer’s disease represents one of the most pervasive, devastating neurodegenerative crises globally. For years, the scientific community has recognized the APOE\varepsilon4 (APOE4) gene variant as the most significant genetic risk factor for the condition. However, possessing the gene is not a guaranteed sentence; rather, it acts as a molecular tripwire. One of the primary mechanisms through which APOE4 destroys cognitive tissue is by unleashing chronic, low-grade brain inflammation (neuro-inflammation) years before structural memory loss ever appears.

To halt this progression, an interdisciplinary team at the USC Center for Personalized Brain Health (CPBH) has identified a promising chemical pathway to turn off this inflammatory cascade before permanent cellular damage occurs.

Key Facts

The cPLA2 Inflammatory Switch: Research directed by Dr. Hussein Yassine isolated a critical culprit in APOE4 carriers who progress to full dementia: elevated levels of an enzyme called calcium-dependent phospholipase A2 (cPLA2). The team has successfully developed small-molecule therapies designed to selectively inhibit cPLA2, quelling inflammation while leaving healthy cellular functions completely untouched.
Deploying AI for Drug Discovery: The Pattiz Fund will heavily back the deployment of advanced artificial intelligence models. These computational tools will rapidly scan and screen thousands of small molecules to find compounds capable of crossing the blood-brain barrier and blocking inflammatory enzymes.
Launching a High-Risk Early Registry: USC will build a specialized early-detection registry mapping individuals at extreme risk for neuro-inflammation. Candidates will be recruited by pairing APOE4 genetic data with known cardiovascular risk factors.
Unlocking the Tissue Library: The funding establishes a protected research window for neuropathologist Dr. Anne Hiniker to audit the USC ADRC Neuropathology Core. Dr. Hiniker will screen more than 1,100 human brain tissue samples to catch and map microscopic inflammatory signposts.
The Recruitment Pipeline: Clinical trials and tracking pipelines will pull high-risk carriers through two established USC networks: GeneScreen (a genetic risk registry) and CPBH SPARK (which tracks how lifestyle vectors influence cognitive aging).
Honoring Two Radio Legends: The fund honors Norman Pattiz, the broadcasting pioneer who founded Westwood One (the nation’s largest radio syndication network), and his wife, Dr. Mary Turner Pattiz, a legendary 1970s Los Angeles rock DJ (“The Burner”) who later earned a PhD in clinical psychology and chaired the Hazelden Betty Ford Foundation. Both passed away recently (2022 and 2023), leaving their board to direct their legacy toward paradigm-shifting medical science.

Source: USC

An interdisciplinary team at the USC Center for Personalized Brain Health (CPBH) is targeting a family of enzymes that can increase the risk of inflammation in the brains of people with the APOE4 gene variation—the most significant genetic risk factor for late-onset Alzheimer’s—as a way to prevent the disease.

By activating or inhibiting the enzymes, the scientists, led by CPBH director Hussein Yassine, MD, have succeeded in identifying a promising pathway to turn off brain inflammation before it does its damage.

Now joining the fight is the Norman and Mary Pattiz Foundation, with a $3 million gift to the Keck School of Medicine of USC that will support promising research, including novel drug discovery and other efforts aimed at early detection and prevention of Alzheimer’s.

The Future in Motion

The newly created Norman and Mary Pattiz Alzheimer’s Research Fund will provide pilot funding and accelerate priority projects of the USC Alzheimer’s Disease Research Center (ADRC). In addition to drug targeting, which includes imaging modality development, and the use of artificial intelligence to pinpoint small molecules involved in brain inflammation, the fund will also support efforts to modernize the center’s brain pathology library and look at brain inflammation markers in patients with Alzheimer’s.

Also made possible by the funding will be a plan to create a registry for early detection of individuals at high risk for neuro-inflammation based on the APOE4 genetic variant and cardiovascular risk factors.

“We are extremely grateful to the Norman and Mary Pattiz Foundation for having the foresight to support research that is breaking new ground,” said Helena Chang Chui, MD, director of the ADRC and the Raymond and Betty McCarron Professor of Neurology.
“That willingness to explore bold hypotheses is what has helped us to make headway in neurodegenerative diseases over the last several years.”

“Norman and Mary Pattiz were trailblazers in their respective careers, and we hope to honor their legacy by carrying that same spirit of innovation and determination into the fight against Alzheimer’s disease,” said Karen Kerrigan, Pattiz Foundation Board President and Norman Pattiz’s former business manager.

Other members of the Foundation Board are three long-time friends and colleagues of Norman Pattiz—Larry Freeman, Paul Krasnow, and Jeff Hershberg. “Each of our Board members has had personal experience with a loved one being impacted by Alzheimer’s disease,” said Freeman, a longtime USC supporter. “We feel certain Norman and Mary would be excited about the potential impact this gift can have in the quest for solutions to this devastating disease.”

The Norman and Mary Pattiz Alzheimer’s Research Fund will recruit APOE4 carriers through USC ARDC’s GeneScreen, an Alzheimer’s prevention registry focused on identifying genetic risk, and CPBH SPARK, a registry focused on understanding how lifestyle and health influences brain aging and the risk of Alzheimer’s disease.

Searching for Clues

The Foundation support also establishes the Norman and Mary Pattiz Foundation Endowed Associate Professorship in Neuropathology, which extends the critical work of neuropathology within the ADRC research endeavors.

The inaugural holder is Anne Hiniker, MD, PhD, director of the USC ADRC Neuropathology Core, where researchers look for signs of disease and disease progression and how changes in the brain may relate to protein accumulations found in Alzheimer’s disease.

The Pattiz Foundation funding will provide Dr. Hiniker with protected research time to speed the capture of inflammation markers or signposts in the more than 1,100 brain tissue samples in the USC ADRC Neuropathology Core.

“I am honored to serve as the inaugural Pattiz Endowed Associate Professor. We hope to do justice to the legacy of Norman and Mary Pattiz with ambitious work designed to set the stage for new therapies for Alzheimer’s disease,” said Dr. Hiniker.

Two Creative Donors

An American broadcasting entrepreneur, Norman Pattiz founded Westwood One, a radio syndication company, in 1976. It became the nation’s largest radio network and a major global media company—leading to Pattiz’s induction into the National Radio Hall of Fame.

Norman Pattiz supported causes he cared deeply about, such as communications, education, and sciences. He served on the Board of Regents of the University of California, as well as the boards of USC Annenberg School for Communication and Journalism, Lawrence Livermore National Laboratory, and the Broadcasting Board of Governors of the United States of America.

Mary Turner Pattiz had her own impressive career as the silky on-air voice of the 1970s and ’80s rock ‘n’ roll era who was known on air as “The Burner, Mary Turner”. As a popular disc jockey, she was credited as part of the soundtrack of that era’s music and was often hailed as the “First Lady of Rock Radio” in Los Angeles. In 2023, Mary received a Legends induction into the Radio Hall of Fame.

She left her career in radio to earn her PhD in clinical psychology and became a certified substance abuse counselor. In 2010, she was elected chair of the Betty Ford Center in Rancho Mirage, California. She was the first non-Ford family member to chair the Center and later oversaw its merger with the Hazelden Foundation in 2013. She remained a Board member of the newly formed Hazelden Betty Ford Foundation for several more years.

Norman and Mary Pattiz passed away in 2022 and 2023, respectively, leaving in place a Board of Directors they entrusted to nurture causes that have meaning in people’s lives. The Board previously funded an endowed chair in ovarian cancer research at the USC Norris Comprehensive Cancer Center. Its latest gift solidifies a significant imprint for the foundation’s legacy within the Keck Medicine of USC ecosystem.

Focusing on Brain Health

The APOE gene is a risk factor but not a guarantee of developing Alzheimer’s disease. In one CPBH study of differences in APOE4 carriers, Dr. Yassine’s team found that people with elevated levels of the enzyme “calcium-dependent phospholipase A2” or cPLA2 developed dementia.

With his collaborators, Dr. Yassine then identified possible drug therapies to selectively target cPLA2, while protecting normal cellular function from adverse effects.

The team wants to expand on that important discovery to find other targets that also trigger neuroinflammation, with potential for developing new drugs for Alzheimer’s.

“Our goal is to determine whether these possible targets and treatment pathways are safe, feasible, and ultimately meaningful for human disease,” said Dr. Yassine.

“Thanks to the generosity of the Norman and Mary Pattiz Foundation, we have a better chance of pursuing these critical questions,” he added, “and finding the answers that can lead us forward.”

Key Questions Answered:

Q: Why is USC focusing on stopping brain inflammation instead of just clearing out the sticky plaques usually associated with Alzheimer’s?

A: For decades, standard Alzheimer’s research focused almost entirely on clearing out amyloid plaques after they formed in the brain, but clinical trials showed that removing these plaques late in the game rarely reversed dementia. The team at USC is changing the timeline. Brain inflammation is the hidden fuel that accelerates the disease. In people with the APOE4 gene, this inflammation acts like a chronic, quiet fire that damages neural connections decades before a patient notices any memory lapses. By using small molecules to turn off the inflammatory enzymes early, USC aims to prevent the fire from starting in the first place, saving the brain’s architecture intact.

Q: What is the cPLA2 enzyme, and how does it act as a “switch” for the disease?

A: The enzyme cPLA2 (calcium-dependent phospholipase A2) acts like an internal alarm system that regulates your body’s inflammatory response. Dr. Yassine’s team discovered that while many people carry the high-risk APOE4 gene, the ones who actually go on to develop severe dementia consistently show highly elevated, overactive levels of this cPLA2 enzyme. It essentially locks the brain’s immune defense system into a permanent, destructive “fight” mode. By engineering new drugs that selectively dial back or inhibit cPLA2, the researchers have found a way to flip this molecular switch back to a safe baseline, protecting normal brain activity while cooling down the toxic inflammation.

Q: How will the $3 million gift from the Pattiz Foundation change how quickly this research moves into actual human treatments?

A: In academic medicine, the transition from identifying a promising molecule to testing it in humans is often stalled by a lack of flexible funding. The Pattiz Foundation gift removes this bottleneck. It provides immediate pilot funding for advanced artificial intelligence to screen for drug candidates, modernizes USC’s 1,100-sample brain tissue library to find new inflammatory markers, and funds a specialized registry to identify and track high-risk APOE4 carriers. This allows the team to rapidly identify the safest, most effective compounds and immediately pair them with the exact patients who need them most, cutting years off the traditional drug development pipeline.