In the U.S. alone, seven million people live with Alzheimer’s disease, yet treatment options remain limited. Although cases are expected to triple by 2050, only a handful of drugs are currently approved by the Food and Drug Administration (FDA), none of which can cure or reverse progression, only manage symptoms.
Motivated by this lack of options, researchers from UC San Francisco and the Gladstone Institutes explored whether already-approved drugs — albeit drugs approved to treat different conditions — might help. Interestingly, a combination of two cancer drugs stood out: Research in mice showed that this combination reduced brain degeneration and restored memory, according to findings recently published in Cell, pointing towards a potent treatment path never considered before.
Genetic Traces of Alzheimer’s
“Alzheimer’s is likely the result of numerous alterations in many genes and proteins that, together, disrupt brain health,” explained Yadong Huang, study co-senior author in a press release. “This makes it very challenging for drug development — which traditionally produces one drug for a single gene or protein that drives disease.”
To tackle this complexity, the team gathered publicly available data from three studies measuring gene expression in brain cells from deceased donors with or without Alzheimer’s. Using these datasets, they created gene expression signatures representing the disease in certain brain cells, then compared them with those in the Connectivity Map, a database cataloguing how thousands of drugs affect gene expression in human cells.
From an initial pool of 1,300 drugs, 86 showed potential to reverse the Alzheimer’s gene expression signature in one brain cell type, and 25 reversed it in several cell types, making it more potent for complex condition like Alzheimer’s. However, only 10 of these drugs had already been approved by the FDA for human use.
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Cancer Drugs to Treat Alzheimer’s?
To narrow the list further, the research team checked anonymized medical records in the UC Health Data Warehouse, covering 1.4 million people over age 65, to see whether any of the promising drugs also reduced the risk of developing Alzheimer’s as a side effect.
“Thanks to all these existing data sources, we went from 1,300 drugs, to 86, to 10, to just 5,” said Yaqiao Li, lead author, in the news release. “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.”
From the top five candidates, the researchers chose two cancer drugs for laboratory testing. They assumed that letrozole, commonly used to treat breast cancer, would improve neuronal health, while irinotecan, used for colon and lung cancer, would benefit glial cells.
Next Step: Clinical Trials
To test their hypothesis, the team used a mouse model for Alzheimer’s disease. Combining both drugs worked wonders: The treatment revoked harmful gene expression signatures in neurons and glia, reduced toxic protein clumps and brain degeneration, and restored memory.
“It’s so exciting to see the validation of the computational data in a widely used Alzheimer’s mouse model,” Huang said, anticipating moving to clinical trial to test the combination therapy in Alzheimer’s patients soon.
“We’re hopeful this can be swiftly translated into a real solution for millions of patients with Alzheimer’s,” added study co-author Marina Sirota in the press statement.
Sirota emphasized how combining computational approaches with existing medical data opens new avenues in drug discovery. “Alzheimer’s disease comes with complex changes to the brain, which has made it tough to study and treat, but our computational tools opened up the possibility of tackling the complexity directly,” she said. “We’re excited that [it] led us to a potential combination therapy for Alzheimer’s based on existing FDA-approved medications.”
This article is not offering medical advice and should be used for informational purposes only.
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Having worked as a biomedical research assistant in labs across three countries, Jenny excels at translating complex scientific concepts – ranging from medical breakthroughs and pharmacological discoveries to the latest in nutrition – into engaging, accessible content. Her interests extend to topics such as human evolution, psychology, and quirky animal stories. When she’s not immersed in a popular science book, you’ll find her catching waves or cruising around Vancouver Island on her longboard.
