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Posted on 07/21/2025 10:47:03 AM PDT by Red Badger
In A Nutshell
* Two FDA-approved cancer drugs — letrozole and irinotecan — significantly improved memory and reduced brain damage in mice with Alzheimer’s.
* The combination therapy targets multiple brain cell types by reversing gene disruptions in neurons and glia.
*Real-world medical records of 1.4 million patients show lower Alzheimer’s rates in people treated with these drugs for cancer.
* The findings offer a new multi-target strategy that may outperform existing single-drug treatments, but human trials are still needed.
SAN FRANCISCO — Two cancer medications already on pharmacy shelves might hold the key to treating Alzheimer’s disease, and early results suggest they work better together than apart.
Researchers at UC San Francisco have found a promising new approach to combating the devastating memory disorder that affects over 50 million people worldwide. Instead of targeting just one aspect of the disease, their strategy attacks multiple brain cell types at once using letrozole, a breast cancer medication, and irinotecan, a colorectal cancer drug.
The breakthrough came from analyzing massive databases of human brain tissue samples and medical records, then testing the combination in mice genetically engineered to develop Alzheimer’s-like symptoms. Only mice receiving both drugs together showed major memory improvements and reduced brain damage.
“Despite rigorous preclinical and clinical research efforts, AD drug development faces significant challenges, with a 98% failure rate in recent decades,” the researchers wrote in their study published in Cell. Their approach marks a departure from traditional single-drug treatments that have repeatedly failed in clinical trials.
How Cancer Drugs Target Neurons and Glial Cells in Alzheimer’s Disease
The drug combination works by addressing what scientists call “cell-type-specific” problems in Alzheimer’s disease. While most research has focused on the sticky plaques and tangled proteins that build up in Alzheimer’s brains, this study looked deeper at how different types of brain cells malfunction in distinct ways.
The research team examined single-cell genetic data from 75 human brain samples – 37 from Alzheimer’s patients and 38 from healthy controls. They discovered that Alzheimer’s affects brain cells unequally. Neurons showed one pattern of genetic disruption, while support cells called glia showed completely different problems.
To identify potential treatments, researchers used a computational approach that contains genetic profiles of how more than 1,300 FDA-approved drugs affect human cells. By matching disease patterns with drug effects, they identified 25 medications that could theoretically reverse Alzheimer’s genetic signatures.
The validation came from analyzing medical records of 1.4 million patients aged 65 and older across six University of California health centers. Among patients who had taken the candidate drugs for their original purposes – cancer treatment, in most cases – five showed much lower rates of developing Alzheimer’s disease compared to matched controls.
Alzheimer’s Memory Improved in Mice Treated With Letrozole and Irinotecan
Eighty mice were divided into four groups receiving either a placebo, letrozole alone, irinotecan alone, or both drugs together. The treatment lasted four months, with drugs given every other day, using clinically relevant doses to better replicate human exposure levels.
Memory testing used the Morris water maze, where mice must remember the location of a hidden platform in a pool of cloudy water. Healthy mice quickly learn to swim directly to the platform’s location, while mice with memory problems swim randomly.
During the learning phase, all groups performed similarly. But when researchers removed the platform and tested whether mice remembered its location, only the combination-treated group showed clear memory retention. These mice spent much more time swimming in the target area and crossed the former platform location more frequently than other groups, both 24 and 72 hours after training.
The memory improvements matched up with dramatic reductions in brain pathology. Combination-treated mice showed increased hippocampal volume – the brain region most affected by Alzheimer’s – along with fewer amyloid plaques and less tau protein accumulation. They also had reduced brain inflammation and better preservation of neurons in critical memory areas.
Medical Record Analysis Shows Lower Alzheimer’s Risk in Cancer Patients
The human medical record analysis backed up the laboratory results. Among breast cancer patients who received letrozole, the rate of Alzheimer’s diagnosis was 53% lower than matched controls. For colorectal cancer patients treated with irinotecan, the rate was 80% lower.
Both drugs can cross the blood-brain barrier, a crucial requirement for treating brain diseases, and the doses used in the mouse study were within human-relevant therapeutic ranges based on prior dosing studies.
To understand how the drugs worked, researchers analyzed gene expression in brain tissue from treated and untreated mice. The combination therapy appeared to reverse many of the genetic changes seen in Alzheimer’s disease, essentially reprogramming diseased brain cells back toward healthy states.
In neurons, the treatment activated genes involved in forming new synapses and maintaining neural connections. In glial cells, it restored genes responsible for supporting neurons, clearing cellular debris, and maintaining brain structure.
The research represents a major shift from current Alzheimer’s treatment approaches. Most existing therapies target amyloid plaques with modest results, while this combination addresses multiple cellular problems simultaneously.
Recent FDA-approved drugs like aducanumab have shown limited effectiveness and significant side effects, leading to widespread criticism and, in some cases, market withdrawal. The cell-type-directed approach could offer a more complete strategy for a disease that involves complex interactions between different brain cell populations.
Several challenges remain before human trials could begin. The mouse model, while sophisticated, may not fully recapture human Alzheimer’s complexity. The study also focused primarily on male mice, as female mice showed less consistent treatment responses – a finding that warrants further investigation given that women face higher Alzheimer’s risk.
For the millions of families affected by this devastating condition, the possibility of transforming readily available cancer medications into memory-preserving treatments offers hope in a field marked by repeated disappointments.
Disclaimer:
This study was conducted in genetically engineered mouse models of Alzheimer’s disease and supported by retrospective analysis of human medical records. While the findings are promising, they do not confirm effectiveness in humans. Clinical trials are necessary to determine safety and efficacy in people with Alzheimer’s disease. Readers should not interpret this research as a recommendation to use cancer drugs for Alzheimer’s prevention or treatment outside of approved contexts.
Paper Summary
Methodology
Researchers integrated single-cell RNA sequencing data from 75 human brain samples to identify cell-type-specific gene expression changes in Alzheimer’s disease. They used computational drug screening against the Connectivity Map database containing 1,300+ FDA-approved drugs, then validated findings using medical records from 1.4 million patients across six UC health centers. For experimental validation, they treated 80 mice (crossing 5×FAD and PS19 Alzheimer’s models) with vehicle, letrozole alone, irinotecan alone, or combination therapy for four months, testing memory with Morris water maze and analyzing brain pathology through immunohistochemistry and single-nucleus RNA sequencing.
Results
The study identified 25 drug candidates that could reverse Alzheimer’s genetic signatures, with five showing reduced dementia risk in human medical records. Letrozole reduced Alzheimer’s risk by 53% and irinotecan by 80% in cancer patients. In mice, only combination therapy significantly improved memory performance and reduced pathology, including increased hippocampal volume, fewer amyloid plaques, reduced tau accumulation, and decreased neuroinflammation. Single-nucleus analysis revealed that combination treatment reversed disease-associated gene expression patterns in multiple brain cell types.
Limitations
The study used cancer cell lines for drug screening rather than brain tissue, mouse models may not fully represent human Alzheimer’s disease complexity, and treatment effects showed significant sex differences with males responding better than females. The electronic medical record analysis involved relatively small patient numbers for some drugs and couldn’t control for all potential confounding factors. Additionally, the treatment duration and optimal dosing for humans remain unclear.
Funding and Disclosures
This research was supported by National Institute on Aging grants (R01AG060393, R01AG057683, RF1AG076647, R01AG078164, P01AG073082), NSF grant 2034836, and the Dolby Family Fund. The authors report that Y. Huang is a co-founder and scientific advisory board member of GABAeron Inc., and Y.L., Y. Huang, and M.S. are co-inventors on a patent application based on this study.
Publication Information
Li, Y., et al. The paper, “Cell-type-directed network-correcting combination therapy for Alzheimer’s disease,” was published in Cell on July 21, 2025.
DOI: 10.1016/j.cell.2025.06.035
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I’m not sure why we’re always saving the mice... But at least somebody is benefitting from it... The mice that live.
I’m pretty sure the mice who die during these ‘experiments’ aren’t too happy.
“Memory Restored? Cancer Drug Combo Reverses Alzheimer’s In Mice”
That’s great for democrats but what about normal people?
None of the mice live, they all get brain autopsied for the final report.
Based on fraudulent research that said Amyloid Beta was the cause.
What have you learned is the cause? Some say it is a form of diabetes of the brain.
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What does your asterisk mean? I don’t know all the posting abbreviations.
Hi, it was just a bookmark for me. Interesting article.
The cause is not known. They found that the amyloid creating the plaques was chemically corrupted. The body creates amyloid to heal the brain. In MS studies, researchers found that amyloid-beta would cure MS in mice. After 13 years, they still haven't tested it on humans. (no money to me made.) I suspect chemically pure amyloid would also cure Alzheimer's.
I see. I just click on “bookmark.”
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