Cancer drugs Letrozole and Irinotecan may reverse Alzheimer’s disease

While searching for Alzheimer’s treatment, scientists at the University of California, San Francisco and the Gladstone Institute have discovered two FDA-approved cancer drugs that may reverse the brain’s molecular decline in Alzheimer’s disease.

These drugs were found to be letrozole and irinotecan, which restored mice’s memory and reduced neurodegeneration by reversing disease gene expression patterns in neurons and glial cells. By repurposing existing drugs and validating them in clinical data and laboratory experiments, the team offers potential new avenues for diseases that affect more than 7 million people in the United States alone.

Computing tools comply with real-world data

Alzheimer’s is driven by complex changes in many brain cell types, so it is difficult to treat with single-target drugs. Therefore, the researchers took a within-scale approach. First, they analyzed the gene activity at single-cell level of Alzheimer’s disease in brain samples from the deceased patients. They then screened over 1,300 compounds in the Connection Map database for drugs that could reverse neuronal and glial changes.

They narrowed the list to 10 FDA-approved drugs. They used anonymous health records of 1.4 million Californians over 65 years of age and found that patients taking certain cancer drugs were less likely to be diagnosed with Alzheimer’s. Two drugs stand out: letrozole for breast cancer and iris cancer for colon cancer.

“Thanks to all these existing data sources, we have increased from 1,300 drugs to 86 to 10 toxins,” said Dr. Yaqiao Li, lead author and postdoctoral scholar at Gladstone. “All the rich data collected by the UC Health Center points us directly to the most promising drugs.”

In the mouse, memory returns

To test the drug, the team used a mouse model of Alzheimer’s disease, designed by human mutations that can produce both amyloid plaques and Tau Tangles, two key markers of the disease. Mice treated with letrozo or ilicon alone showed limited improvement. But when combined, these drugs:

• Greatly reduces the accumulation of toxic tau
• Changes in reverse gene expression of neurons and glia
• Saving short-term and long-term memory in water maze test
• Reduce inflammation and brain cell loss

Letrozole mainly improves neuronal health, while irinotecan reduces glial-driven inflammation. Together, they targeted different arms of the disease and provided two supporting treatment strategies.

“It is exciting to see validation of computational data in a widely used Alzheimer’s mouse model,” said Dr. Yadong Huang, director of the Gladstone Center for Transformational Development.

Genetic Network tells this story

Further analysis of mouse brains suggests that this treatment reverses the genetic network of altered Alzheimer’s disease. In neurons, genes related to synaptic signaling and dendritic growth are restored. In glia, key pathways associated with oxidative stress, cholesterol metabolism, and inflammation have been restored to balance.

Importantly, researchers noted that combination therapy does not simply mask symptoms. It corrects the underlying molecular procedures driving the disease in at least mice.

“We hope this can quickly turn it into a real solution for millions of Alzheimer’s patients,” said Marina Sirota, PhD, collaborative side effects and interim director of the Bakar Computation Sealtical Sciences Institute at UCSF.

Are you ready for a human test?

Although these findings are promising, the team stresses that testing people with Alzheimer’s disease needs to be done before any conclusions are drawn. Both Letrozole and Irinotecan have known side effects and are currently used in cancer patients. However, their existing safety profiles, along with real-world data, suggest that the risk of Alzheimer’s is reduced, allowing them to repurpose forcefully.

Researchers are now laying the foundation for clinical trials. If successful, this could mark a rare moment in Alzheimer’s study: a plaque-removing therapy, but rather a restoration of the brain’s molecular integrity in many of its cell types.

Looking to the future

This study demonstrates the power of combining big data, computational biology and drug reuse to solve a disease as complex as Alzheimer’s. Rather than chasing a single goal, the approach recognizes the diversity of the disease and aims to correct it at the cellular network level.

“If a completely independent data source, such as single-cell expression data and clinical records, guide us to the same pathway and the same medications and then solve Alzheimer’s in a genetic model, then maybe we are using something.”

Posted in cell July 21, 2025. DOI: 10.1016/j.cell.2025.07.018

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