With Alzheimer’s disease affecting over 30 million people globally, researchers are racing against time to discover therapies that not only manage symptoms but alter the course of the disease. Now, a team of scientists has found that two existing cancer drugs may hold surprising potential to do just that.
Published recently in Cell, the study reveals that letrozole and irinotecan, medications typically used to treat breast and colorectal cancers, may reverse key brain cell changes in Alzheimer’s—offering hope for a disease that currently has no cure.
The approach is known as drug repurposing: finding new uses for already-approved drugs with known safety profiles. “The beauty of repurposing is speed,” said Marina Sirota, PhD, co-senior author and professor at UCSF’s Bakar Computational Health Sciences Institute. “We already know how these drugs behave in the body. Now the question is, can they help in a completely different disease?”
Mapping the Molecular Footprint of Alzheimer’s
The study began by analyzing how Alzheimer’s disease disrupts gene activity in different types of brain cells—especially neurons and glial cells, the latter being critical supporters of brain function. Researchers used data from human brain tissue to identify the unique “gene expression signature” left behind by the disease.
Then, turning to a massive drug-response database called ConnectivityMap, they searched for compounds that could reverse these molecular patterns—essentially restoring the cells’ gene activity to a more normal state.
Out of 1,300 drugs, letrozole and irinotecan emerged as top candidates.
To validate their findings beyond the lab bench, the team examined electronic health records from patients across the University of California medical system. They discovered that individuals who had taken either drug had a significantly lower risk of developing Alzheimer’s.
Lab Mice, Real Hope
Encouraged by the data, the team tested the drug combination in a mouse model engineered to develop aggressive Alzheimer’s-like symptoms. The results were striking.
The dual therapy not only reversed the disease’s gene expression signature but also reduced levels of amyloid-beta and tau—the toxic proteins that accumulate in the brains of Alzheimer’s patients. Mice treated with the drug combo showed improvements in memory-related behaviors and less neurological damage.
“These findings align across molecular data, clinical history, and animal models,” Sirota said. “It’s a rare trifecta in early drug discovery.”
A Glimpse into the Mechanism
Letrozole, an aromatase inhibitor, blocks estrogen production and is commonly used in postmenopausal breast cancer. Irinotecan, on the other hand, targets DNA replication in rapidly dividing cancer cells by inhibiting the enzyme topoisomerase I.
Though their primary actions are well understood, their effects on brain function in the context of Alzheimer’s remain speculative. “We don’t yet know whether these effects are direct or off-target,” Sirota cautioned. “More mechanistic studies are essential before moving to clinical trials.”
Experts Weigh In
Independent experts see promise in this innovative strategy. Dr. John Dickson, a neurologist at Massachusetts General Hospital, called the study “a compelling example of how big data and molecular biology can converge to find new uses for old drugs.”
Dr. Clifford Segil of Providence Saint John’s Health Center added, “It’s refreshing to see memory loss addressed through a novel mechanism unrelated to acetylcholine or amyloid—a space where so many therapies have stumbled.”
And for Dr. Peter Gliebus, director of cognitive and behavioral neurology at Marcus Neuroscience Institute, the advantage of repurposing is clear. “These drugs already have established safety profiles, which can speed up development and reduce cost. That’s crucial in a field where so many new compounds have failed.”
What’s Next?
While the findings are still in early stages, they represent a critical leap forward. The researchers are already planning additional studies in human populations to understand how, when, and in whom this drug combo might work best.
Until then, this study stands as a beacon of cautious optimism—an example of how existing tools, used creatively, might carve new paths toward treating one of the world’s most devastating diseases.
