As Alzheimer’s cases surge worldwide and current therapies offer only limited relief, scientists are exploring bold new strategies—including repurposing cancer drugs—to disrupt the disease’s progression. A groundbreaking study out of the University of California, San Francisco (UCSF) delves into whether established oncology medications could effectively counteract neurodegeneration and cognitive decline in Alzheimer’s.
Why look to cancer drugs?
The vast complexity of Alzheimer’s means it alters the expression of numerous genes across different brain cell types. Instead of pursuing a single-target therapy, UCSF researchers adopted a systems-driven approach, analyzing gene expression profiles in human brain cells and matching them against effects seen in more than 1,300 FDA-approved medications—from antibiotics and antipsychotics to various chemotherapy drugs.
From this massive dataset, 86 drugs showed potential to reverse Alzheimer’s-related gene-expression signatures in vitro. Further filtering via electronic health records from over 1.4 million older adults narrowed the list to five candidates that were associated with lower Alzheimer’s incidence.
Ideal drug duo: Letrozole + Irinotecan
The top two contenders: letrozole, a breast cancer medication that influences neuronal gene expression, and irinotecan, typically used in colon and lung cancer that modulates glial cells—the brain’s support structure.
Importantly, retrospective analyses demonstrated that patients using these drugs had a reduced risk of developing Alzheimer’s: a 2020 letrozole cohort and 2021 irinotecan cohort both experienced slower disease onset.
When tested together in Alzheimer’s mouse models, the duo reversed hallmark signs of the disease: tau tangles decreased, brain degeneration slowed, and memory performance showed measurable improvement.
How do they work?
There are several leading hypotheses:
Hormonal regulation: Letrozole inhibits estrogen, which may rebalance thousands of genes affected in Alzheimer’s.
Inflammation control: Irinotecan may limit inflammation by modulating glial cell proliferation, suppressing toxic overactivation.
Metabolic restoration: As suggested by external experts, the combo may also rejuvenate glucose metabolism in brain cells—critical for neural communication
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Yet, it remains unclear if the drugs act synergistically or via independent pathways; the mechanisms are still under investigation.
Next steps: Moving toward human tests
This repurposing strategy could significantly accelerate the timeline to clinical use. While developing a novel drug often spans over a decade and exceeds a billion dollars, leveraging approved medications typically takes 2–3 years before clinical trials can begin.
UCSF researchers are preparing for early-phase human trials to assess whether the benefits seen in mice can be replicated in people with mild Alzheimer’s. However, tolerability will be a key consideration: letrozole is associated with hormonal side effects like hot flashes, and irinotecan is known for gastrointestinal issues such as diarrhea and nausea.
Broader drug-repurposing landscape
This effort isn’t unique. Other studies have demonstrated similar promise:
Penn State/Stanford teams have shown that inhibitors of the enzyme IDO1—initially developed for cancers like melanoma and leukemia—can restore memory in Alzheimer’s models by improving glucose metabolism in astrocytes.
A recently published epidemiological analysis found that HIV medications (NRTIs) might reduce Alzheimer’s risk by inhibiting inflammatory pathways, potentially preventing around 1 million cases annually.
Meanwhile, UCSF and Vanderbilt are investigating a range of compounds, all aimed at reducing inflammation, modulating protein aggregation, or rebalancing gene expression networks.
Challenges ahead
Alzheimer’s remains one of the most elusive neurodegenerative diseases. Despite the encouraging animal data, there’s no guarantee these outcomes will translate to human patients. Safety profiles must be carefully evaluated, especially given the potential toxicity of cancer drugs.
Nonetheless, this approach—integrating computational biology, real-world medical data, and repurposed therapeutics—offers a compelling blueprint for accelerating Alzheimer’s treatment discovery.
