Can Two Cancer Drugs Really Reverse Alzheimer’s?

July 21, 2025

Experimental Alzheimer’s treatment using letrozole and irinotecan reversed neural damage and restored memory in mice./ Pexels

Scientists at UCSF and Gladstone Institutes unveiled a novel discovery on July 21, 2025 in the journal Cell. They compared gene‑expression signatures from Alzheimer’s‑affected human brain cells against those provoked by 1 300 FDA‑approved drugs, identifying two cancer medications—letrozole and irinotecan—that could reverse key molecular hallmarks of Alzheimer’s in mice.

From Data Mining to Validation in Mice

1. Building Alzheimer’s Gene Expression Profiles

Researchers analyzed single‑cell gene expression from three independent public datasets of post‑mortem human brains. Neurons and glial cells displayed distinct disease signatures, capturing genetic shifts tied to Alzheimer’s neurodegeneration

2. The Connectivity Map Screening

This dataset—known as the Connectivity Map—contains transcriptome profiles of >10 000 drugs in human cells. Among these, 86 drugs reversed Alzheimer’s signatures in at least one cell type, 25 did so across multiple types, but only 10 were FDA‑approved.

3. Real‑World Confirmation via Health Records

Using the UC Health Data Warehouse (1.4 million patients over age 65), the team found that individuals prescribed certain candidate drugs exhibited a significantly lower incidence of Alzheimer’s—demonstrating “mock clinical trial” evidence.

4. Testing in an Alzheimer’s Mouse Model

When letrozole (breast‑cancer drug) and irinotecan (colon‑/lung‑cancer drug) were administered together in a genetically engineered Alzheimer’s mouse model, results showed:

Reversal of disease‑associated gene expression in neurons and glia.
Reduction of amyloid‑ and tau‑protein clumping.
Noteworthy improvement in memory and cognition.

These combined effects far exceeded results from either drug given alone.

Expert Insights: Why This Study Is a Turning Point

Dr. Marina Sirota (UCSF) commented that their integrative computational approach “opened up the possibility of tackling complexity directly,” and the mouse model reversal marks a major milestone.

Dr. Yadong Huang (Gladstone, UCSF) noted the challenge Alzheimer’s poses due to its multifactorial nature: “Numerous alterations in many genes and proteins…makes drug development very challenging.” The dual-drug strategy offers a fresh path forward .

Dr. Yaqiao Li, lead author, summed up the methodology: “We went from 1 300 drugs, to 86, to 10, to just 5… rich data … pointed us straight to the most promising drugs. It’s kind of like a mock clinical trial” .

Implications and Next Steps: Toward Human Trials

This combination drug strategy aligns with the modern trend toward precision medicine, tackling Alzheimer’s as a system‑level disorder rather than a single‑target disease. Since both letrozole and irinotecan have known safety profiles, the time to potential clinical trials could be shorter .

The authors stress this as the earliest, yet critical, step toward human studies: preclinical success must now be tested in patients to confirm safety, optimal dosing, and actual cognitive benefit.

Comparisons to Existing Alzheimer’s Treatments

To date, only two FDA‑approved Alzheimer’s drugs exist, neither of which substantially alters disease progression. Unlike monoclonal antibodies such as lecanemab or donanemab, which target amyloid plaques with mixed cognitive outcomes, this combination takes a broader molecular approach .

Challenges and Considerations

Mouse models ≠ humans: Animal success often fails in human trials.
Drug side effects: Combining letrozole and irinotecan may increase adverse effects like nausea and fatigue.
Dosing strategies: Optimal timing, dose, and duration need definition.
Biomarkers & subgroups: Identifying who benefits most—based on genetics, stage, or biomarkers—will be critical.

Conclusion: A Promising Milestone, But Not a Cure—Yet

This study represents a major leap in Alzheimer’s research by:

Using single‑cell gene expression to map disease signatures.
Leveraging big data and health records for drug candidate validation.
Demonstrating reversal of Alzheimer’s hallmarks in an animal model.

While these results are exciting, the true test will be in well‑designed human trials. If successful, this repurposing strategy could accelerate development time and reduce cost—offering renewed hope for millions affected by Alzheimer’s.

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