Cancer Drugs Letrozole and Irinotecan May Reverse Alzheimer’s

In a surprising turn in the search for Alzheimer’s therapies, scientists at UC San Francisco and the Gladstone Institutes have identified two FDA-approved cancer drugs that may reverse the brain’s molecular decline in Alzheimer’s disease.

The drugs, letrozole and irinotecan, were found to restore memory and reduce neurodegeneration in mice by reversing the disease’s gene expression patterns across neurons and glial cells. By repurposing existing medications and validating them in both clinical data and lab experiments, the team offers a potential new path forward in treating a disease that affects more than 7 million people in the United States alone.

Computational Tools Meet Real-World Data

Alzheimer’s is driven by complex changes in many brain cell types, making it hard to treat with single-target drugs. So the researchers took a systems-wide approach. First, they analyzed how Alzheimer’s alters gene activity at the single-cell level in brain samples from deceased patients. Then they screened over 1,300 compounds in the Connectivity Map database, searching for drugs that reverse those changes in neurons and glia.

They narrowed the list to 10 FDA-approved drugs. Using anonymized health records from 1.4 million Californians over age 65, they found that patients who had taken certain cancer drugs were less likely to be diagnosed with Alzheimer’s. Two drugs stood out: letrozole, used for breast cancer, and irinotecan, used for colon cancer.

“Thanks to all these existing data sources, we went from 1,300 drugs, to 86, to 10, to just 5,” said Yaqiao Li, PhD, lead author and postdoctoral scholar at Gladstone. “The rich data collected by all the UC health centers pointed us straight to the most promising drugs.”

In Mice, Memory Returns

To put the drugs to the test, the team used a mouse model of Alzheimer’s engineered with human mutations that produce both amyloid plaques and tau tangles—two key hallmarks of the disease. Mice treated with either letrozole or irinotecan alone showed limited improvements. But when combined, the drugs:

• Significantly reduced toxic tau buildup
• Reversed gene expression changes in both neurons and glia
• Rescued short-term and long-term memory in water maze tests
• Reduced inflammation and brain cell loss

Letrozole primarily improved neuronal health, while irinotecan reduced glial-driven inflammation. Together, they appeared to target different arms of the disease, offering a two-pronged therapeutic strategy.

“It’s so exciting to see the validation of the computational data in a widely used Alzheimer’s mouse model,” said Yadong Huang, MD, PhD, co-senior author and director of the Center for Translational Advancement at Gladstone.

Gene Networks Tell the Story

Further analysis of the mice’s brains showed that the treatment reversed the very gene networks altered by Alzheimer’s. In neurons, genes tied to synaptic signaling and dendrite growth were restored. In glia, key pathways tied to oxidative stress, cholesterol metabolism, and inflammation were brought back into balance.

Importantly, the researchers noted that the combination therapy didn’t simply mask symptoms. It corrected the underlying molecular programs driving the disease, at least in mice.

“We’re hopeful this can be swiftly translated into a real solution for millions of patients with Alzheimer’s,” said Marina Sirota, PhD, co-senior author and interim director of UCSF’s Bakar Computational Health Sciences Institute.

Ready for Human Trials?

While the findings are promising, the team emphasizes that the drugs need to be tested in people with Alzheimer’s before any conclusions can be drawn. Both letrozole and irinotecan have known side effects and are currently used in cancer patients. But their existing safety profiles, combined with real-world data suggesting lower Alzheimer’s risk, make them strong candidates for repurposing.

Researchers are now laying the groundwork for clinical trials. If successful, this could mark a rare moment in Alzheimer’s research: a therapy based not on removing plaques, but on restoring the brain’s molecular integrity across its many cell types.

Looking Ahead

This study showcases the power of combining big data, computational biology, and drug repurposing to tackle diseases as complex as Alzheimer’s. Rather than chasing a single target, the approach recognizes the disease’s diversity—and aims to correct it at the cellular network level.

“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,” said Sirota.

Study published in Cell on July 21, 2025. DOI: 10.1016/j.cell.2025.07.018