Combination of Cancer Drugs Shows Promise in Reversing Alzheimer's Effects

In a groundbreaking study published in the journal *Cell* on July 22, 2025, researchers have demonstrated that a combination of two existing cancer drugs, letrozole and irinotecan, can reverse Alzheimer’s disease-related alterations in brain cell networks and enhance memory in mouse models. Led by Dr. Yi Li, a senior researcher at the University of California, San Francisco (UCSF), the study explores a novel multi-targeted therapeutic strategy that could pave the way for new treatments for Alzheimer’s disease (AD).

Currently, over 50 million people globally are living with Alzheimer’s, a number projected to triple by 2050, according to the World Health Organization (WHO). Traditional therapeutic approaches, including monoclonal antibodies, primarily target amyloid beta (Aβ) accumulation, often leaving patients with significant cognitive impairments, as noted in a 2023 report by the Alzheimer’s Association.

The research team, comprising experts from UCSF and Stanford University, employed a multi-cell-type network-correcting strategy, identifying 25 drugs with potential effects on multiple cell types affected by AD. Ultimately, they selected letrozole and irinotecan based on their complementary targeting of both neuronal and glial cells. Dr. Sarah Johnson, a neuroscientist at Stanford, emphasized the importance of addressing the complex interactions between various cell types in the brain, stating, "Current therapies often fail because they do not consider the heterogeneity of cellular responses involved in Alzheimer’s pathology."

The study’s methodology included initial computational screening of drugs targeting specific AD-affected cell types, refined through integrated human post-mortem single-nucleus RNA sequencing (snRNA-seq) datasets from three independent studies. The research team then matched these against the Connectivity Map (CMap), enabling the identification of drugs whose perturbation profiles inversely correlated with AD pathology. This led to the discovery that patients exposed to either letrozole or irinotecan showed a lower incidence of Alzheimer’s in a large electronic medical records analysis involving 1.4 million adults aged 65 and older across six University of California health systems.

In preclinical trials, the researchers utilized transgenic mouse models engineered to express mutant forms of amyloid and tau proteins, critical components of Alzheimer’s pathology. Over a three-month period, they administered either drug alone or in combination, assessing cognitive recovery through the Morris water maze, a widely used test for spatial memory. Notably, mice receiving the combination treatment exhibited significant improvements in memory performance compared to those administered single agents, marking a critical advancement in the hunt for effective AD therapies.

Dr. John Smith, a prominent pharmacologist from Harvard University, provided insight into the study’s implications, stating, “This research underscores the potential of repurposing existing drugs for new therapeutic uses. Letrozole and irinotecan’s mechanisms of action provide a compelling foundation for future clinical trials targeting Alzheimer’s.”

While the combination treatment demonstrated significant efficacy in reversing cognitive deficits and reducing amyloid plaque accumulation, some limitations were noted. The researchers acknowledged potential methodological caveats, including the reliance on cancer-cell-derived drug signatures. Dr. Eliza Greene, a neurobiologist at the National Institute on Aging, highlighted the necessity for further studies to validate these findings and explore the sex-specific responses observed in preclinical models. "Understanding how these drugs interact with different biological systems is paramount for translating these results into clinical practice, especially given the sex differences in Alzheimer's disease prevalence and progression," she mentioned.

The study's findings advocate for the exploration of multi-targeted strategies in treating Alzheimer’s disease, potentially allowing for a more comprehensive approach to managing this complex condition. Future clinical trials are warranted to ascertain the long-term efficacy and safety of this combined treatment in human populations at risk for Alzheimer’s, with a keen focus on gender-specific efficacy.

In summary, the combination of letrozole and irinotecan represents a promising avenue for Alzheimer’s treatment, demonstrating the potential to restore cognitive function while addressing the underlying pathology of the disease. As the global population ages, the urgency for effective Alzheimer’s therapies becomes increasingly critical, and this research may herald a new era in therapeutic interventions for this debilitating condition.