By Morgan Nwanguma
A new study has uncovered a potential breakthrough in Alzheimer’s treatment by repurposing existing cancer drugs. Researchers compared the gene expression patterns of Alzheimer’s disease with those triggered by 1,300 FDA-approved medications and identified a promising combination of two cancer therapies.
Scientists at UC San Francisco and the Gladstone Institutes found that these drugs could reverse the harmful gene expression changes seen in neurons and glial cells—the brain cells most affected by Alzheimer’s. By analyzing how the disease alters gene activity at the single-cell level, they pinpointed medications that might counteract those changes.
To strengthen their findings, the team also reviewed millions of electronic medical records and discovered that patients who had taken some of these cancer drugs for other conditions were less likely to develop Alzheimer’s.
In animal testing, the drug combination produced striking results: in mouse models of Alzheimer’s, it reduced brain degeneration and even restored memory function.
This research suggests that repurposed cancer drugs could one day help slow or reverse the progression of the most common form of dementia.
“Alzheimer’s disease comes with complex changes to the brain, which has made it tough to study and treat, but our computational tools opened up the possibility of tackling the complexity directly,” said Marina Sirota, PhD, the interim director of the UCSF Bakar Computational Health Sciences Institute, professor of pediatrics, and co-senior author of the paper. “We’re excited that our computational approach led us to a potential combination therapy for Alzheimer’s based on existing FDA-approved medications.”
The study was published in Cell on July 21 and was supported in part by the National Institutes of Health and the National Science Foundation.
Big data reveals a potential new therapy for Alzheimer’s
Alzheimer’s disease, which affects an estimated 7 million people in the United States, drives a steady loss of memory, learning, and cognitive function. Despite decades of research, only two FDA-approved drugs exist, and neither significantly slows the disease’s progression.
“Alzheimer’s is likely the result of numerous alterations in many genes and proteins that, together, disrupt brain health,” said Yadong Huang, MD, PhD, senior investigator and director of the Center for Translational Advancement at Gladstone, professor of neurology and pathology at UCSF, and co-senior author of the paper. “This makes it very challenging for drug development — which traditionally produces one drug for a single gene or protein that drives disease.”
The researchers began by analyzing publicly available datasets from three studies of Alzheimer’s disease, which measured single-cell gene expression in brain tissue from deceased donors with and without the condition. From this, they created detailed gene expression “signatures” for Alzheimer’s in both neurons and glial cells.
They then compared these disease signatures with data in the Connectivity Map—a large database cataloging how thousands of drugs alter gene expression in human cells. Of the 1,300 drugs screened, 86 were found to reverse Alzheimer’s-related gene expression in at least one brain cell type, and 25 reversed it across multiple cell types. Only 10 of these drugs, however, were already FDA-approved.
To test whether these findings translated into real-world outcomes, the team examined anonymized medical records from 1.4 million people over age 65 in the UC Health Data Warehouse. They discovered that several of the identified drugs were associated with a reduced risk of developing Alzheimer’s over time.
“Thanks to all these existing data sources, we went from 1,300 drugs, to 86, to 10, to just 5,” said Yaqiao Li, PhD, a former UCSF graduate student in Sirota’s lab who is now a postdoctoral scholar in Huang’s lab at Gladstone and the lead author of the paper. “In particular, the rich data collected by all the UC health centers pointed us straight to the most promising drugs. It’s kind of like a mock clinical trial.”
A combination therapy moves closer to primetime
From the top drug candidates, Li, Huang, and Sirota selected two cancer medications for laboratory testing: letrozole, typically prescribed for breast cancer, and irinotecan, commonly used against colon and lung cancers. Based on their predictions, letrozole would target disease processes in neurons, while irinotecan would act on glial cells.
The researchers tested the drugs in a mouse model of aggressive Alzheimer’s carrying multiple disease-related mutations. As the mice aged and developed Alzheimer’s-like symptoms, they were treated with either one drug or the combination.
The results were striking: the two-drug combination reversed several hallmarks of Alzheimer’s in the mice. It reset the abnormal gene expression patterns in both neurons and glia, reduced toxic protein clumps and brain degeneration, and—most significantly—restored memory function.
“It’s so exciting to see the validation of the computational data in a widely used Alzheimer’s mouse model,” Huang said. He expects the research to advance soon to a clinical trial so the team can directly test the combination therapy in Alzheimer’s patients.
“If completely independent data sources, such as single-cell expression data and clinical records, guide us to the same pathways and the same drugs, and then resolve Alzheimer’s in a genetic model, then maybe we’re onto something,” Sirota said. “We’re hopeful this can be swiftly translated into a real solution for millions of patients with Alzheimer’s.”
Authors: Other UCSF researchers include Carlota Pereda Serras, MS, Jessica Blumenfeld, Xinyu Tang, PhD, Antara Rao, PhD, Sarah Woldemariam, PhD, Alice Tang, PhD, Tomiko Oskotsky, MD, and Michael J Keiser, PhD. Other Gladstone Institutes authors are Min Xie, PhD, Yanxia Hao, Elise Deng, You Young Chun, Julia Holtzman, Alice An, Seo Yeon Yoon, MBA, Alex Zhang, Jeffrey Simms, MA, and Iris Lo.
financial support: This research was backed by the National Institute on Aging (R01AG060393, R01AG057683, RF1AG076647, R01AG078164, and P01AG073082), the National Science Foundation (2034836), and the Dolby Family Fund.
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