Do these two cancer drugs have what it takes to beat Alzheimer's?

Scientists at the UC San Francisco and Gladstone Institutes have identified two cancer drugs that show promise in reversing the changes that occur in the brain during Alzheimer's , potentially slowing or even reversing its symptoms. The findings were published Monday in the journal Cell.

The study first analyzed how Alzheimer's disease altered gene expression in individual brain cells. Researchers then looked for drugs already approved by the U.S. Food and Drug Administration (FDA) that cause opposite changes in gene expression.

They were specifically looking for drugs that would reverse changes in gene expression in neurons and other types of brain cells called glia, all of which are damaged or altered in Alzheimer's disease.

Researchers then analyzed millions of electronic medical records to show that patients taking some of these drugs as part of their treatment for other conditions were less likely to develop this neurodegenerative disease.

When they tested a combination of the two leading drugs (both anticancer) in a mouse model of Alzheimer's, they slowed brain degeneration in the mice and even restored their ability to remember .

“Alzheimer’s disease involves complex changes in the brain, which has made it difficult to study and treat, but our computational tools opened the possibility of addressing this complexity directly,” said Marina Sirota, Ph.D., interim director of the UCSF Bakar Computational Health Sciences Institute, professor of pediatrics, and co-senior author of the paper. “We are excited that our computational approach has led us to a potential combination therapy for Alzheimer’s based on existing FDA-approved drugs.”

Alzheimer's disease affects 7 million people in the United States. In Spain, approximately 800,000 people live with the disease , and approximately 40,000 new cases are diagnosed each year. It causes relentless decline in cognition, learning, and memory. However, decades of research have produced only two FDA-approved drugs , neither of which can significantly slow this decline.

“Alzheimer’s disease is likely the result of numerous alterations across many genes and proteins that collectively disrupt brain health. This poses a challenge for treatment development, as traditionally, a single drug has been developed for a single gene or protein that triggers the disease,” said Yadong Huang, Ph.D., principal investigator and director of the Center for Translational Advancement at Gladstone, professor of neurology and pathology at UCSF, and co-senior author on the paper.

The team compiled publicly available data from three Alzheimer's brain studies that measured single-cell gene expression in brain cells from deceased donors with and without the condition. They used this data to generate gene expression signatures for Alzheimer's disease in neurons and glia.

The researchers compared these signatures to those found in the Connectivity Map, a database of test results of the effects of thousands of drugs on gene expression in human cells.

Of 1,300 drugs, 86 reversed gene expression characteristic of Alzheimer's disease in one cell type, and 25 reversed it in multiple brain cell types. However, only 10 of them had yet been approved by the FDA for use in humans.

Examining records housed in the UC Health Data Warehouse, which includes anonymized health information on 1.4 million people over the age of 65, the group found that several of these medications appeared to have reduced the risk of developing Alzheimer's disease over time.

“Thanks to all these existing data sources, we went from 1,300 drugs to 86, to 10, to just 5,” said Yaqiao Li, PhD, a former UCSF graduate student in Sirota’s lab who is now a postdoctoral researcher in Huang’s lab at Gladstone and lead author on the paper. “In particular, the wealth of data collected across all UC Health centers allowed us to directly identify the most promising drugs. It’s like a simulated clinical trial,” he concludes.

Li, Huang, and Sirota selected two cancer drugs from the top five candidates for laboratory testing. They predicted that one drug, letrozole , would cure Alzheimer's in neurons; and another, irinotecan , would help glia. Letrozole is commonly used to treat breast cancer ; irinotecan is used to treat colon and lung cancer.

The team used a mouse model of aggressive Alzheimer's with multiple associated mutations. As the mice aged, they exhibited Alzheimer's-like symptoms and were treated with one or both drugs.

The combination of both cancer treatments reversed multiple aspects of Alzheimer's in the animal model, dismantled gene expression signatures in neurons and glia that had emerged with disease progression, reduced both the formation of toxic protein clumps and brain degeneration; and, most importantly, restored memory .

"It's very exciting to see the validation of the computational data in a widely used mouse model of Alzheimer's," Huang said. He hopes the research will soon advance to a clinical trial so the team can directly test the combination therapy in Alzheimer's patients.

"If completely independent data sources, such as single-cell expression data and clinical histories, guide us toward the same pathways and the same drugs, and then resolve Alzheimer's in a genetic model, then perhaps we are on the right track. We hope this can quickly translate into a real-world solution for millions of Alzheimer's patients," Sirota concludes.