Scientists Find Way to Reverse Alzheimer's Brain Changes with Cancer Drugs

Scientists from UC San Francisco and the Gladstone Institutes have identified anti-cancer drugs that may reverse the changes that occur in the brain in Alzheimer's disease, potentially slowing or even reversing its symptoms.

In a study published in Cell, scientists compared the gene expression signature of Alzheimer's disease with changes caused by 1,300 approved drugs and found a combination of two cancer drugs that could treat the most common form of dementia.

The study first analyzed how Alzheimer's disease alters gene expression in individual cells in the human brain. The researchers then looked for existing drugs, already approved by the Food and Drug Administration (FDA), that cause the opposite changes in gene expression.

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

The researchers then analyzed millions of electronic medical records and showed that patients who took some of these drugs as part of their treatment for other conditions were less likely to develop Alzheimer's disease.

When they tested a combination of the two top drugs - both of which are anti-cancer agents - in a mouse model of Alzheimer's disease, it reduced brain degeneration in the mice and even restored their memory ability.

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

Big data from patients and cells points to new Alzheimer's therapy

Alzheimer's disease affects 7 million people in the U.S. and causes a steady decline in cognitive function, learning, and memory. Yet decades of research have yielded only two FDA-approved drugs, neither of which can significantly slow the decline.

“Alzheimer’s disease is likely the result of multiple changes in many genes and proteins that work together to disrupt brain health,” said Yadong Huang, MD, PhD, a senior scientist and director of the Gladstone Translational Research Center, a UCSF professor of neurology and pathology, and a co-author of the paper.
“This makes drug development extremely challenging, since traditionally drugs have been designed to target a single gene or protein that causes the disease.”

The team used publicly available data from three Alzheimer's brain studies that measured gene expression in individual brain cells from deceased donors with and without Alzheimer's. They used this data to create gene expression signatures for Alzheimer's in neurons and glia.

The researchers then compared these signatures with results from the Connectivity Map database, which contains data on the effects of thousands of drugs on gene expression in human cells.

Of 1,300 drugs:

• 86 reversed the Alzheimer's disease gene expression signature in one cell type.
• 25 reversed it in several types of brain cells.
• Only 10 have already been approved by the FDA for use in humans.

Analyzing data from the UC Health Data Warehouse (anonymized information on 1.4 million people over age 65), the team found that several of these drugs appeared to reduce the risk of developing Alzheimer's disease over time.

“With all these existing data sources, we narrowed the list from 1,300 drugs to 86, then to 10, and finally to five,” said Yaqiao Li, PhD, a former graduate student in Sirota’s lab at UCSF, now a postdoctoral fellow in Huang’s lab at Gladstone and lead author of the paper.
“The particularly rich data collected by all UC medical centers immediately pointed us to the most promising drugs. It’s kind of like a simulated clinical trial.”

Combination therapy ready for next step

Li, Huang, and Sirota selected two anticancer drugs from the top five candidates for lab testing. They hypothesized that one drug, letrozole, might help neurons, and the other, irinotecan, might help glia. Letrozole is commonly used to treat breast cancer, and irinotecan is used to treat colon and lung cancer.

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

The combination of two anti-cancer drugs reversed several aspects of Alzheimer’s in this animal model. It eliminated the gene expression signatures in neurons and glia that emerged as the disease progressed. It reduced the formation of toxic protein clumps and brain degeneration. And, crucially, it restored memory.

“It’s exciting to see the computational data confirmed in a widely used mouse model of Alzheimer’s disease,” Huang said. He expects the research to soon move into a clinical trial to directly test the combination therapy in patients.

“If completely independent data sources, like gene expression data in single cells and medical records, point us to the same pathways and the same drugs, and then those drugs are effective in a genetic model of Alzheimer’s disease, then maybe we’re really on the right track,” Sirota said.
“We’re hopeful that this can be quickly translated into a real solution for millions of Alzheimer’s patients.”