Alzheimer’s disease is one of the most enigmatic brain afflictions and among the greatest health care challenges facing the nation. It affects more than 7 million Americans — a number projected to double by 2060. This article is the first in the series “USC United Against Alzheimer’s: Collaborating in Research and Care,” which illustrates how USC researchers and clinicians are making groundbreaking strides in the treatment, prevention and care of Alzheimer’s.

You misplace your keys. You struggle to remember the name of an acquaintance. You forget an important appointment.

From time to time, everyone experiences lapses in memory. But in midlife, as such blunders become more frequent, they can trigger fear about the future. Alzheimer’s disease, which affects 1 in 9 people age 65 and older, is a progressive neurodegenerative disease that slowly robs people of their memory, thinking skills and ability to function independently. And there is no known cure.

“Alzheimer’s is the most feared consequence of aging,” says Paul Aisen, founding director of the USC Epstein Family Alzheimer’s Therapeutic Research Institute (Epstein ATRI).

But now, for the first time in the 120-year history of Alzheimer’s disease research, prevention of this devastating neurodegenerative disease is within reach. New early-detection strategies and medications — many of which are being developed at and in collaboration with USC — offer hope for disease intervention years before people begin to lose memory and cognitive function.

In 2023, lecanemab, the first drug approved by the FDA to slow the progression of early-stage Alzheimer’s disease in those with mild symptoms, came on the market. After decades of setbacks and slow progress in the search for treatments, this breakthrough — developed with work by USC scientists — ushered in a new era of excitement among the research community.

“Everything feels different the last few years, compared with the decades leading up to that,” says Aisen, who has been studying the disease for nearly 40 years.

Aisen and his Epstein ATRI colleagues are leading a global, multicenter clinical trial, called the AHEAD Study, that is investigating whether lecanemab can slow or stop Alzheimer’s brain changes before symptoms emerge. Other clinical trials in the works will test whether experimental therapies refined at ATRI can intervene even earlier, at the first domino in the cascade of Alzheimer’s brain changes.

“The long-term goal is to monitor everybody in middle age to identify those headed for Alzheimer’s disease before there is any degeneration in the brain to cause cognitive symptoms,” says Aisen, professor of neurology at the Keck School of Medicine of USC and Epstein Alzheimer’s Disease Director’s Chair. “When the abnormalities start, we’re going to fix them with medications, just as we lower cholesterol in midlife to prevent heart attacks and stroke. That’s primary prevention.”

Attaining this goal will require more research into the factors that trigger Alzheimer’s, reliable diagnostic tests suitable for widespread use, and effective therapies to stop or reverse disease processes. Aisen is confident that these benchmarks can be achieved within a remarkable timeframe: the next 10 years. Part of his optimism stems from the culture of collaboration within Epstein ATRI and across USC, where researchers in a variety of disciplines are deeply engaged in every facet of this objective.

Much of the groundbreaking work happening at the university is brought to life by the generosity of donors. “The Trojan Family continues to step up by providing the philanthropic support needed to stop this terrible disease,” USC President Beong-Soo Kim says. “If and when we cure Alzheimer’s, the generosity and vision of USC’s donors and supporters will have made all the difference in the world.”

Daniel J. Epstein and his family’s contributions, for example, have catalyzed next-generation clinical trials, data sharing and Epstein ATRI’s research into blood biomarkers.

A ‘powerhouse’ in Alzheimer’s research

USC has long been a leader in the fight against Alzheimer’s. The USC Leonard Davis School of Gerontology, the nation’s oldest and largest gerontology school and a trailblazer in Alzheimer’s research, was founded in 1975. In 1984, the National Institute on Aging funded the USC Alzheimer’s Disease Research Center (USC ADRC) as one of five inaugural sites for a network that has grown to 38 centers.

Today, USC has many Alzheimer’s-focused interdisciplinary research centers that work together. USC ARDC, Epstein ATRI, the USC Mark and Mary Stevens Neuroimaging and Informatics Institute, the USC Zilkha Neurogenetic Institute and the USC Center for Personalized Brain Health are research hubs that unite faculty across disciplines ranging from molecular and systems biology to neurology, gerontology, biomedical engineering and more.

“Few institutions in the United States — or the world — bring this level of powerhouse expertise together in true collaboration,” says Arthur Toga, the Ghada Irani Chair in Neuroscience at Keck School of Medicine and director of the USC Stevens Neuroimaging and Informatics Institute. “That’s a unique feature of USC; it’s very advantageous because we get to relate what we’re doing to another point of view, another approach.”

The institute was endowed by longtime USC benefactors Mark and Mary Stevens in 2015, who called the field of neuroscience “the next great frontier of medical research in the 21st century.”

Toga ­and his collaborators at the Laboratory of Neuro Imaging (LONI) developed the Image and Data Archive, a tool to facilitate real-time data sharing among thousands of brain researchers worldwide, thereby accelerating discovery. Pharmaceutical companies used data from the archive, which holds the most widely used repository of Alzheimer’s disease observational data in the world, to develop lecanemab and design clinical trials for the drug.

Another premier resource that enables collaboration at a global scale is the Epstein ATRI Biomarker Lab and Biorepository, housed in the Epstein ATRI Neuroscience Translational Research Division (NTRD). This division, led by founding director Robert Rissman, professor of physiology and neuroscience and the W.M. Keck Endowed Chair in Medicine, conducts experiments in model systems to develop new treatments for Alzheimer’s disease and related dementias and develops new blood-based biomarkers for clinical trials. The Epstein ATRI Biorepository is among the largest in the field, currently holding about 5 million samples of human plasma and other specimens collected from clinical trials and longitudinal studies worldwide.

“Working together is how we’ve made progress on understanding Alzheimer’s, how we’ve gotten to effective disease-slowing medications — and how we will get to primary prevention,” Aisen says.

 

Finding the Alzheimer’s ‘smoking gun’

Alzheimer’s disease is characterized by two hallmark changes in the brain that interfere with the communication between brain cells: plaques made of a protein called beta-amyloid, and tangles made of a protein called tau. The buildup of these proteins begins at least 15 years prior to the emergence of dementia symptoms. By the time someone shows up at their doctor’s office forgetting important dates or struggling to find words, typically around age 65 or older, plaques and tangles are already well established in the brain.

Scientists have not reached consensus on what causes these proteins to accumulate, but USC researchers are at the forefront of pinpointing the inciting events, a fundamental step in primary prevention.

Mara Mather ­— professor of gerontology at USC Leonard Davis; psychology at the USC Dornsife College of Letters, Arts and Sciences; and biomedical engineering at the USC Viterbi School of Engineering — studies an area of the brain called the locus coeruleus. This small brain-stem region could be “ground zero” of Alzheimer’s. “It is the first place that Alzheimer’s pathology is seen in postmortem brains,” Mather says. A precursor to the tau tangles associated with Alzheimer’s, called hyperphosphorylated tau, has been found in the locus coeruleus in children as young as 11 months old.

The locus coeruleus is the main source of noradrenaline in the brain. Noradrenaline is the key player in the body’s “fight or flight” system, which becomes hyperactive as we age. Mather’s research suggests a link between noradrenergic hyperactivity and increased beta-amyloid production in the brain during middle age.

At Epstein ATRI, Aisen and Rissman are studying how the amyloid production pathway takes a turn toward toxic beta-amyloid buildup. “What starts off the amyloid abnormalities is aberrant cleavage of a protein called the amyloid precursor protein,” Aisen says.

“By measuring different fragments of amyloid precursor protein in blood, we can see that amyloid protein accumulation has increased, and that indicates that someone is headed for this disease,” Rissman says.

Helena Chui — director of USC ADRC and Raymond and Betty McCarron Professor and Chair of Neurology at Keck School of Medicine — is a pioneer in studying how the health of the brain’s vascular system is relevant to Alzheimer’s disease. This vast network of blood vessels supplies oxygen and nutrients to the brain and clears waste substances from it. Stiffening of these vessels due to aging and factors like high cholesterol, high blood pressure, diabetes and the accumulation of amyloid in blood vessels themselves can contribute independently to cognitive impairment. These vascular changes can occur decades before the clinical onset of Alzheimer’s.

At LONI, Toga and his research team program radio frequency pulses for magnetic resonance imaging (MRI) to visualize the blood-brain barrier, a membrane that prevents harmful substances in the blood from reaching the brain. These advanced imaging techniques have provided new insights into how dysfunction of the blood-brain barrier sets the stage for tau and beta-amyloid buildup.

Genetics also plays a major role in early Alzheimer’s brain changes. Hussein Yassine, professor of neurology and gerontology at Keck School of Medicine and director of the USC Center for Personalized Brain Health, studies people who carry a relatively common genetic variant called APOE ε4, which elevates their risk of the disease. This variant accelerates the buildup of beta-amyloid in the brain and its blood vessels. It appears to trigger a change in how the brain processes lipids (fats), leading to chronic inflammation that depletes its defensive resources. “Ultimately, the immune cells in the brain are not able to clear the plaques and tangles, and you get spread of the disease by that mechanism,” Yassine says.

Developing a test for widespread use

Screening everyone regularly at midlife for the earliest signals of Alzheimer’s will require testing methods that are accessible, cost-effective and minimally invasive. Current tools for detecting amyloid and tau pathologies don’t yet fit the bill.

Cerebrospinal fluid tests require an uncomfortable spinal tap. Positron emission tomography (PET) brain scans, which involve the injection of a radioactive tracer, are costly and typically only available in major academic or research-focused health care settings.

“The most exciting development of the last few years is the field of blood-based biomarkers,” Rissman says. “Studies have determined that we can find proteins related to things going on in the brain that you can detect in the blood. I think we’re going to see almost a complete replacement of some of the more invasive or expensive techniques.”

Aisen and Rissman envision that blood-based biomarker tests will become part of routine bloodwork ordered for annual physical exams, facilitating early and widespread detection.

Drawing on samples from the vast Epstein ATRI Biorepository, Rissman and his colleagues have refined and validated a blood test for a form of tau called phospho-tau217. Phospho-tau217 predicts whether someone has amyloid deposits in their brain long before they exhibit Alzheimer’s symptoms. The test, which has accuracy comparable to PET scans and spinal fluid tests, was used to help screen participants for the AHEAD Study, thereby accelerating enrollment.

Rissman’s team is also working to validate a new assay platform that measures multiple biomarkers in the blood associated with amyloid buildup and changes to the synapses, which are junctions between nerve cells in the brain.

Another USC research team led by Ebrahim Zandi, associate professor of molecular microbiology and immunology at Keck School of Medicine, has developed a low-cost blood test that detects five biomarkers of Alzheimer’s disease simultaneously. Zandi tested this platform for accuracy in samples from the USC ADRC Biomarker Core, a lab also led by Rissman that analyzes, stores and shares biofluids from USC ADRC studies.

While these blood tests are primarily focused on detecting amyloid and tau, Chui and Vasilis Marmarelis, Dean’s Professor of Biomedical Engineering at USC Viterbi, are exploring an alternative diagnostic tool. Alzheimer’s disease is associated with an impairment in the ability of blood vessels to naturally constrict or dilate, a critical function for regulating blood flow in the brain and ensuring proper oxygen and nutrient delivery. Marmarelis applied sophisticated mathematical modeling to develop the Cerebrovascular Dynamics Index (CDI), a novel and highly sensitive measure of blood flow velocity and brain oxygenation in brain arteries. Though more research is needed to determine CDI’s significance in clinical settings, early results suggest that the test can distinguish people with Alzheimer’s from controls.

 

Measuring cognition at midlife

About 30% of older adults with enough beta-amyloid and tau in their brains to receive an Alzheimer’s diagnosis never develop any declines in memory or thinking. Consequently, biomarker tests may not provide a complete picture of an individual’s risk level. Additional tests are likely needed to tease out which individuals with hallmarks of Alzheimer’s pathology will go on to develop dementia and which won’t.

More vigilant cognitive testing is crucial. A recent study by Soeren Mattke, director of the USC Brain Health Observatory and research professor of economics at USC Dornsife, found that approximately 7.4 million Americans have undiagnosed mild cognitive impairment and aren’t getting the care that could slow or prevent the advancement to more severe impairment.

Duke Han — professor of psychology and family medicine at USC Dornsife — researches the earliest cognitive signs of dementia and serves as co-primary investigator on the Open Measures Network Initiative for Alzheimer’s Disease and Related Dementia Research and Prevention. The nationwide initiative’s goal is to develop innovative tests to monitor cognitive health in midlife and identify early warning signs years before dementia symptoms emerge. Offered on a digital platform, the open-source tests will be available for use in clinics, community centers and homes.

“The overarching goal is to make sure that the tools are accessible to all different community members, particularly underserved populations who are most at risk for Alzheimer’s disease,” says Han, noting that compared to older white adults, older Black adults are twice as likely to develop Alzheimer’s disease and older Hispanic adults are 1.5 times more likely to do so.

Developing drugs to halt the disease

Lecanemab and donanemab ­— the second drug approved by the FDA (in 2024) for early-stage Alzheimer’s ­— have been shown to slow progression of the disease by about 30%. These monoclonal antibodies target beta-amyloid deposits and enable the immune system to clear the deposits away. They’re an exciting step forward, but they aren’t what’s needed to achieve primary prevention.

“To prevent the disease, we have to use drugs not targeting the amyloid deposits, because there aren’t yet any amyloid deposits,” Aisen says. “We have to use drugs that fix the process that leads to amyloid deposition in the brain. So, we need to move in a different direction.”

Aisen and his colleagues at Epstein ATRI are among the USC researchers developing and refining new drugs and drug protocols. The Epstein ATRI team is investigating the safety and efficacy of two existing classes of drugs known to fix the aberrant cleavage of the amyloid precursor protein. Aisen estimates that clinical trials for primary prevention will begin within the next few years.

Recruiting participants for Alzheimer’s clinical trials has been historically challenging. Research led by Dana Goldman — University Professor at the USC Price School of Public Policy and founding director of the USC Schaeffer Institute for Public Policy & Government Service — shows that Alzheimer’s trials are longer, slower and more costly to recruit for than other therapeutic areas. Primary prevention trials present unique recruitment challenges because participants cannot be identified based on symptoms they haven’t yet developed. Aisen and Goldman collaborate on designing, piloting and evaluating innovative recruitment strategies to overcome these barriers at the Clinical Trial Recruitment Lab.

An interdisciplinary team of researchers led by Yassine is developing a new drug aimed at a previously unexplored biological target. Yassine found that APOE ε4 carriers with elevated levels of the enzyme cPLA2 go on to develop dementia, while those without elevated levels remain cognitively healthy. The team discovered a small molecule that effectively blocks the enzyme in the brain and appears to be a promising candidate for a novel drug.

Pinchas Cohen — dean of USC Leonard Davis and Distinguished Professor of gerontology, medicine and biological sciences — and his collaborators have identified a series of microproteins produced by the mitochondria inside cells that naturally decrease with age and whose decline is linked to the onset of age-­related diseases, including Alzheimer’s disease. A mutation in one of these tiny proteins, called SHMOOSE, is prevalent in nearly a quarter of people of European ancestry and increases the risk of Alzheimer’s by up to 50%. “Our goal is to develop SHMOOSE itself as a drug that is a precision fit for people with the mutation,” Cohen says.

At the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, Paul Seidler, assistant professor of pharmacology and pharmaceutical sciences, is researching therapeutic agents to inhibit the buildup of tau. While amyloid builds up in the gray matter and blood vessels, tau accumulates inside the neurons themselves. Seidler and his lab team have discovered that certain neurotransmitters inside nerve cells can break up fibers of tau, as do a series of synthetic chemicals they’ve identified. In animal studies, these molecules show promise for unraveling established tau tangles and preventing tau from accumulating in the first place.

Seidler believes he and his colleagues at USC are working at the cusp of a revolution in Alzheimer’s prevention that will change the course of the disease — and the course of history.

“I think we’re living in an exciting time right now, and I think people don’t fully appreciate it yet because it’s only the very beginning,” Seidler says. “I think we’ll look back on this eventually and say, ‘That was the watershed moment.’”

Actor Noah Wyle has been playing doctors on television for much of his more than three-decade career, most recently as Michael “Robby” Robinavitch in the Emmy Award-winning HBO Max emergency-r oom drama, The Pitt.

On Monday, at the first-ever Arts + Health: A USC Arts Now Symposium, Wyle spoke about how witnessing the show’s resonance with its millions of viewers has sharpened his understanding of how art shapes our views on health and health care providers.

“I think people are tuning in to be reminded that there are dedicated, intelligent, compassionate, complex people that are out there, day in and day out, putting our broken pieces together, compartmentalizing their own trauma to do so — and oftentimes don’t get any of the credit,” said Wyle, who also serves as a writer, director and executive producer on the series.

His commentary went to the heart of the half-day symposium’s theme: “the power of the arts as a tool for medical knowledge, for healing, for wellness,” said Josh Kun, USC vice provost for the arts and professor and chair in cross-cultural communication at the USC Annenberg School for Communication and Journalism.

Kun co-organized the event — held at the Dr. Allen and Charlotte Ginsburg Human-Centered Computation Hall on the USC University Park Campus and attended by more than 400 people — with Michele Kipke, USC associate senior vice president for strategic health initiatives at the office of the senior vice president for health affairs, and Shrikanth Narayanan, USC vice president for presidential initiatives and University Professor.

Through panel discussions, demonstrations, performances and a keynote conversation with Kun, Wyle and other special guests from The Pitt, the symposium drew attention to groundbreaking interdisciplinary arts-and-health collaborations within USC and with scientists and artists outside the university. Dance, music, painting, comedy, cinema, gaming and narrative were among the creative forms represented throughout the day’s talks, alongside medical fields including neurology, radiology, oncology and more.

With its six conservatory-level arts schools, five health schools and academic medical system, USC is a unique incubator for innovations in arts and healing. “USC is very ideally suited for promoting and advancing excellence across these domains,” Narayanan said.

Health meets Hollywood at USC Arts + Health symposium

Co-sponsored by USC’s arts and humanities initiative Visions and Voices, the symposium was presented by USC Arts Now, a presidential initiative led by Kun to foster projects and programming that put USC’s arts schools and resources into new, unexpected collaborations with each other and connect fields as disparate as health sciences, computing and the arts. Another aim is to link USC faculty and students to artists, arts industries and arts institutions in Los Angeles and around the world.

The Pitt is a prime example of an artistic work informed by USC expertise. Wyle and the other Pitt panelists explained how the show’s gritty realism is made possible in part by a collaboration between the show and Hollywood, Health and Society, a program of the USC Annenberg Norman Lear Center. Since 2001, the program has provided the entertainment industry with accurate and up-to-date information for storylines on health, safety and security. It connects The Pitt’s creative staff to specialized health professionals to help them gain an inside perspective on medical scenarios that inform storylines.

“Getting the perspective from The Pitt’s showrunner, actor, writer and medical consultant allowed us to see how they each approach the creation of one scene to be both medically accurate and narratively exciting,” said Tara Sandman-Long, a senior at the USC Jimmy Iovine and Andre Young Academy who attended the symposium. “It was as if I was watching an operation in real time as each individual panelist broke down their specific piece and how what they brought to the table made the show what it was.”

USC Arts + Health symposium: Dancing, singing, clowning around

Patrick Corbin, associate professor of practice at the USC Kaufman School of Dance, got the symposium audience on their feet for an impromptu dance during his morning presentation. Following his cues, participants stepped side to side, waved their hands in the air and spun in circles. Corbin’s instructions were drawn from dance classes he has taught alongside USC students to older adults with Parkinson’s disease, children with Down syndrome, people with autism, and other vulnerable communities.

“Dancing facilitates several things within our brains across all of these domains: sensory, motor, cognitive, social, emotional, rhythmic, creative,” Corbin said. “When we’re dancing together, we share that reward and create connections with each other.”

Corbin’s series of adaptive dance classes is among a robust collection of USC programs that use the arts in creative and evidence-based ways to provide comfort and healing to patients and support health across the lifespan. Other programs represented at the symposium included the Institute for Arts in Medicine (I_AM) at the USC Norris Comprehensive Cancer Center, which offers a wide range of expressive arts programming to improve clinical outcomes for cancer patients; USC Comic+Care, a program at the USC School of Dramatic Arts that employs medical clowns in hospitals to support children grappling with illness; USC Narrative Medicine at the Keck School of Medicine of USC, where workshops have helped cancer patients engage in reflective writing and create community poems with healing themes; and the Creative Media & Behavioral Health Center, a collaboration between the USC School of Cinematic Arts and Keck School of Medicine that has created virtual reality games for rehabilitating spinal cord injury patients and Parkinson’s disease patients.

Music-based programs discussed at the symposium included the Aging Minds Project at the Center for Music, Brain and Society at the USC Dornsife College of Letters, Arts and Sciences, which assesses how participating in a choir and listening to music influences well-being in older adults; and the Cochlear Implant Music Hour presented by the Bionic Ear Lab at Keck School of Medicine, which helps cochlear implant users to rediscover music through weekly virtual sessions with guest musicians.

“Health and healing do not just happen in clinics and hospitals,” Kipke said. “They happen in communities, in relationships, in identity and in the way in which we make meaning of life.”

Telling stories, saving lives

Jeremy Kagan, professor at School of Cinematic Arts, and Sheila Murphy, professor at USC Annenberg, showed two short films at the symposium that shared identical facts about women’s gynecological health screenings. One was an informational documentary, the other a dramatic narrative of several generations of women in a family discussing their health while making tamales. Both films were made by Kagan and Murphy’s Change Making Media Center at School of Cinematic Arts, which uses filmmaking as a tool for promoting social, health and environmental change.

The symposium audience erupted in laughter at humorous, poignant moments in the tamale-making film, demonstrating its relatability. Prior research conducted at the center showed that female viewers learned equally from both films, but the narrative was more effective than the documentary in motivating viewers to make potentially lifesaving doctor’s appointments.

“By using good stories that entertain, you can potentially shift awareness and even change behavior,” Kagan said. “Facts inform, but stories transform.”

Few fields reveal medicine’s storytelling power more vividly than radiology, which produces “pretty pictures” that resemble art — all while exposing unseen truths about the body.

At the panel “Radiology Live,” Summer Decker — professor of clinical radiology at Keck School of Medicine and director of the school’s Center for Innovation in Medical Visualization — joined her associate director, Jonathan Ford, associate professor of clinical radiology, to share what CT scans uncovered about a 2,300-year-old Egyptian mummy: a life full of stories untold.

Visual artist Edgar Arceneaux, associate professor and chair of art at the USC Roski School of Art and Design, rounded out the conversation, tracing parallels between the studio and the scan room. The trio explored how art sharpens medicine — improving surgical precision and deepening patient understanding — while medical imaging, in turn, gives artists new ways to grapple with mortality and meaning.

“It’s been really special for us to remember that this [mummy] was a person walking around on the earth; someone loved them and cared for them,” Decker said, noting how this understanding extends to all radiology patients. “Every day, as we’re looking at these images, we remind ourselves that these are people. We’re about to impact someone’s life. And we can tell their story.”

The transformational possibilities of creating and consuming art for individual health and collective well-being proved to be a unifying message for the day.

“The short, exciting presentations gave insights into specifically how narrative affects whether someone would go to the doctor and walked us through the power of dance to the mind,” Sandman-Long said. “I was able to learn specific knowledge that I could take with me, not just a general understanding that art and medicine can somehow be connected.”