Cancer drug could treat early-stage Alzheimer’s, study finds

A type of drug developed to treat cancer shows promise as a new treatment for neurodegenerative diseases such as Alzheimer’s, according to a study by researchers at Penn State, Stanford University and an international team of collaborators.

The researchers found that by blocking a specific enzyme called indoleamine-2,3-dioxygenase 1, or IDO1 for short, they could rescue memory and brain function in models that mimic Alzheimer’s disease.

The results, published on August 22 in the journal Sciencesuggest that IDO1 inhibitors currently being developed as treatments for many types of cancer, including melanoma, leukemia and breast cancer, could be repurposed to treat early stages of neurodegenerative diseases – a first for chronic diseases that lack preventative treatments.

“We show that there is strong potential for IDO1 inhibitors, which are already part of the pipeline of drugs in cancer treatment, to target and treat Alzheimer’s disease,” said Melanie McReynolds, the Dorothy Foehr Huck and J. Lloyd Huck Early Career Chair in Biochemistry and Molecular Biology at Penn State and a co-author of the paper.

“In the broader context of aging, neurological decline is one of the major factors preventing healthier aging. The benefits of understanding and treating metabolic decline in neurological disorders will impact not only those diagnosed, but also our families, our society, and our economy as a whole.”

Alzheimer’s disease is the most common type of dementia, an umbrella term for all age-related neurodegenerative disorders, McReynolds explained. As of 2023, as many as 6.7 million Americans were living with Alzheimer’s, according to the Centers for Disease Control and Prevention, and its prevalence is expected to triple by 2060.

“Inhibiting this enzyme, particularly with compounds that have already been studied in human clinical trials for cancer, could be a big step forward in finding ways to protect our brains from damage caused by aging and neurodegeneration,” said Katrin Andreasson, the Edward F. and Irene Pimley Professor of Neurology and Neurological Sciences at Stanford University School of Medicine and senior author of the study.

Alzheimer’s disease affects the parts of the brain that control thought, memory and language, resulting from a progressive and irreversible loss of synapses and neural circuits.

As the disease progresses, symptoms can worsen, ranging from mild memory loss to loss of the ability to communicate and respond to the environment. Current treatments for the disease aim to manage symptoms and slow progression by targeting the buildup of amyloid and tau plaques in the brain, but there are no approved treatments to combat the onset of the disease, McReynolds said.

“Scientists targeted the downstream effects of what we identify as a problem with how the brain feeds,” said Praveena Prasad, a doctoral student at Penn State and co-author of the paper.

“Currently available therapies aim to eliminate peptides that are likely the result of a larger problem that we can target before these peptides start to form plaques. We are demonstrating that by targeting brain metabolism, we can not only slow, but reverse the progression of this disease.”

Using preclinical models (in vitro cellular models with amyloid and tau proteins, in vivo mouse models, and in vitro human cells from Alzheimer’s disease patients), the researchers demonstrated that knocking down IDO1 helps restore healthy glucose metabolism in astrocytes, the star-shaped brain cells that provide metabolic support to neurons.

IDO1 is an enzyme that breaks down tryptophan, the same molecule in turkey that can make you sleepy, into a compound called kynurenine. The body’s production of kynurenine is the first part of a chain reaction known as the kynurenine pathway, or KP, which plays a critical role in how the body delivers cellular energy to the brain.

The researchers found that when IDO1 produced too much kynurenine, it reduced glucose metabolism in astrocytes, which are needed to fuel neurons. With IDO1 removed, metabolic support for neurons increased and restored their ability to function.

The researchers conducted the study on several models of Alzheimer’s pathology, namely amyloid or tau accumulation, and found that the protective effects of IDO1 blockade extend to these two different pathologies.

Their findings suggest that IDO1 may also be relevant in diseases with other types of pathology, such as Parkinson’s disease and dementia, as well as in the broad spectrum of progressive neurodegenerative disorders known as tauopathies, said Paras Minhas, a current resident at Memorial Sloan Kettering Cancer Center who received a combined MD and PhD in neuroscience from Stanford School of Medicine and is the paper’s first author.

“The brain relies heavily on glucose to fuel many processes. Therefore, loss of the ability to efficiently use glucose for metabolism and energy production can trigger metabolic decline and, in particular, cognitive decline,” Minhas said. “Through this collaboration, we were able to precisely visualize the impact of neurodegeneration on brain metabolism.”