Alzheimer’s Breakthrough: Cancer Drugs Reverse Memory Loss in Mice
A pioneering study reveals that a combination of two repurposed cancer drugs shows remarkable promise in restoring memory and correcting brain cell dysfunction in mice models of Alzheimer’s disease, hinting at a new era of multi-targeted therapies.
Targeting Brain Cell Networks
Researchers explored combining letrozole, an aromatase inhibitor, with irinotecan, a topoisomerase I inhibitor. Their goal was to reverse specific transcriptomic disturbances identified in various brain cell types affected by Alzheimer’s disease (AD), ultimately aiming to improve cognition and reduce disease pathology.
A Complex Challenge
Dementia affects millions globally, with Alzheimer’s disease projected to triple its prevalence by 2050. Current treatments, primarily monoclonal antibodies targeting amyloid-beta, offer limited cognitive benefits, underscoring the need to address the intricate dysfunctions across neurons and glial cells, which are intricately linked in AD progression.
Repurposing for Faster Intervention
The strategy of repurposing existing, approved drugs offers a potentially faster and safer path to new treatments. However, many existing therapies focus on single targets, failing to address the broad cellular heterogeneity observed in AD. This study specifically sought to correct multi-cell-type network imbalances.
Identifying Promising Candidates
The research team identified 25 drugs with predicted multi-cell-type effects. Further analysis of human clinical records revealed that only five correlated with a reduced risk of AD. Among these, letrozole and irinotecan were chosen for their complementary potential in targeting both neuronal and glial cells, offering hope for a dual-action approach.
Preclinical Validation
To test their hypothesis, scientists utilized mouse models genetically engineered to mimic key aspects of Alzheimer’s disease. Mice received either a placebo, letrozole, irinotecan, or the combination therapy over three months. Cognitive function was assessed using the Morris water maze, and brain tissue was analyzed for key pathological markers and transcriptomic changes.
Cognitive Recovery and Reduced Pathology
The study’s results were striking. While individual drugs showed some benefits, the combination therapy significantly restored both short- and long-term spatial memory in the mice. This dual treatment also demonstrated superior effects in preserving hippocampal volume, reducing both amyloid-beta plaques and, crucially, phosphorylated tau, a hallmark of AD progression. Furthermore, the combination therapy modulated glial inflammation and preserved neuronal loss, with synergistic effects observed.
Rewiring Gene Networks
At the molecular level, parallel hippocampal single-nucleus RNA sequencing confirmed that the combined regimen effectively rewired disease-specific gene networks across multiple cell types. The treatment normalized gene expression, including APOE in microglia, astrocytes, and oligodendrocyte precursor cells, and reversed neuronal gene expression associated with estrogen signaling and synaptic plasticity, while glial gene expression changes pointed to reduced oxidative stress and improved cholesterol transport.
Future Directions
The findings suggest that this repurposed combination therapy offers a powerful, cell-type-directed strategy for Alzheimer’s disease. While promising, further research is needed to confirm these results in human clinical trials, with a particular focus on understanding and addressing any sex-specific efficacy differences observed in the preclinical models. According to the Alzheimer’s Association, over 6 million Americans are currently living with Alzheimer’s disease, a number projected to nearly double by 2060 (Alzheimer’s Association, 2024).
