Two FDA-Approved Cancer Drugs, Combined, Reduce a Key Alzheimer’s Protein in Mice — 1.4M Health Records Helped Point the Way

Two existing cancer drugs show promise against an Alzheimer’s hallmark in preclinical tests

Treating Alzheimer’s disease likely requires a multipronged approach that targets several molecular pathways. In a new study led by researchers at UC San Francisco (UCSF) and published in Cell, scientists combined computational gene-expression screening with real-world clinical data to identify two FDA-approved cancer drugs that, together, reduced accumulation of abnormal tau protein in mouse models of Alzheimer’s.

The team began by comparing how Alzheimer’s changes gene expression across different brain cell types and then searched for drugs that produced the opposite patterns. From roughly 1,300 candidate compounds, the computational screen narrowed the list to drugs that reversed disease-associated expression changes in one or multiple cell types.

Next, the researchers cross-referenced those computational hits with outcomes in a large clinical dataset: the UC Health Data Warehouse, containing about 1.4 million anonymized electronic health records for people aged 65 and older. That real-world analysis highlighted two drugs in particular: letrozole (commonly used in breast cancer) and irinotecan (used for colon and some lung cancers).

“Thanks to all these existing data sources, we went from 1,300 drugs, to 86, to 10, to just 5,” said lead author Yaqiao Li, a UCSF graduate student. “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.”

In mouse Alzheimer’s models, the combination of letrozole and irinotecan reduced buildup of abnormal tau protein — a hallmark pathology associated with neuronal dysfunction and cognitive decline. Researchers propose that letrozole may act on neurons while irinotecan could affect glial cells, the brain’s non-neuronal support cells, addressing disease processes across cell types.

“Alzheimer’s is likely the result of numerous alterations in many genes and proteins that, together, disrupt brain health. This makes it very challenging for drug development—which traditionally produces one drug for a single gene or protein that drives disease,” said UCSF co-author Yadong Huang. “It’s so exciting to see the validation of the computational data in a widely used Alzheimer’s mouse model.”

Important caveats: the positive signal from electronic health records is observational and does not prove causation, and efficacy so far is limited to animal models. Both letrozole and irinotecan are systemic cancer therapies with known side effects and toxicity profiles that must be carefully evaluated in older adults. The results are promising as a drug-repurposing lead, but rigorous clinical trials are required to determine safety, dosing, and whether the combination actually slows cognitive decline in people with or at risk for Alzheimer’s.

Because both drugs are already FDA-approved for other indications, the researchers hope the path to clinical trials could be accelerated. If validated in humans, a combination approach targeting multiple cell types and pathways could become part of a broader strategy to address the complex biology of Alzheimer’s disease.

Bottom line: Computational screening plus large-scale health records pointed researchers to two existing cancer drugs whose combination reduced abnormal tau in mice. The finding is an encouraging step toward repurposing approved drugs for Alzheimer’s, but human trials and careful safety assessment are essential before any clinical use.