Brain neuron death occurs throughout life and increases with age, a natural human protein drug may halt neuron death in Alzheimer’s disease

(Press-News.org) AURORA, Colo. (Dec. 19, 2025) – Scientists at the University of Colorado Anschutz have discovered that while brain neuron changes, including cell loss, may begin in early life, a drug long-approved for other conditions might be repurposed to slow this damage, offering new hope for those with Alzheimer’s disease (AD) and other cognition issues.

The study was published today in the journal Cell Reports Medicine.

“This drug improved one measure of cognition and reduced a blood measure of neuron death in people with AD in a relatively short period of time in its first clinical trial,” said the study’s senior author Professor Huntington Potter, PhD, director of the University of Colorado Alzheimer’s and Cognition Center at CU Anschutz.

The drug, sargramostim (also called LeukineÒ), a synthetic form of the natural human protein GM-CSF, has been used for 30 years to treat a variety of conditions including cancer. It has also shown promise in its first clinical trial by improving blood biomarkers of brain pathology. The biomarker improvement lasted only as long as the drug was taken, yet the memory improvement on one measure lasted longer.

The new study, co-authored by Stefan Sillau, PhD, Christina Coughlan, PhD and Md. Mahiuddin Ahmed, PhD, and colleagues, revealed in a cross-sectional study of people of all ages that a protein released into the blood from dying brain neurons, called UCH-L1, and another protein released from damaged neurons, called NfL, are at low concentrations in the blood in early life and their levels are exponentially higher every year through age 85. Early life changes in this biomarker likely reflect a normal process of aging, but in later stages of life, increases in UCHL-1 are linked with poorer outcomes. This discovery could lead to earlier testing and new therapies for AD and possibly for cognitive decline due to normal aging.

The researchers also found that the concentration of the protein GFAP, a measure of brain inflammation that is thought to play a key role in driving cognitive decline, is significantly higher in the blood starting at age 40. Interestingly, age-associated blood concentrations of GFAP and UCH-L1 are higher in women for reasons that remain unclear.

“These findings suggest that the exponentially higher levels of these markers with age, likely accelerated by neuroinflammation, may underlie the contribution of aging to cognitive decline and AD and that sargramostim treatment may halt this trajectory,” Potter said.

The natural GM-CSF protein stimulates the immune system, causing it to create new immune cells in the bone marrow and brain, while modulating inflammation. In animal models, Potter said, “GM-CSF also reverses cognitive decline and the rate of neuron death after just a few weeks of treatment.”

“When people with AD were given sargramostim in the clinical trial, their blood levels of the UCH-L1 measure of neuronal cell death dropped by 40% - in our study, this was similar to levels seen in early life,” Potter said. “We were very surprised.”

Sargramostim treatment also led to improved scores on one of the cognitive tests performed, the Mini-Mental State Exam (MMSE), compared to those taking a placebo. Other cognitive tests showed no change.

Whether the drug will reduce Alzheimer-associated neuronal damage only with continuous use is unclear and needs more study. At 45 days after treatment ended, the blood UCH-L1 concentration had returned to pre-treatment levels but the improvement in the MMSE measure of cognition was retained. More research will also be needed to determine if the drug can reduce normal age-associated neuron death and cognitive decline.

The authors remind people that results from this study are still preliminary and that changes in blood neuronal markers are expected to occur throughout life as a normal part of aging. A second, longer and more extensive clinical trial with the drug in mild-to-moderate AD participants is currently underway. Until the clinical research is completed and the FDA considers the data and approves sargramostim for treating Alzheimer’s, the drug should not be prescribed or taken for any non-approved use.

The other co-authors include Neill Epperson, Timothy Boyd, Joaquin Espinosa, Kavita Nair, Paula Araya, Matthew D. Galbraith, Alanna Ritchie, Athena Ching-Jung Wang, Mihret T. Elos, Brianne M. Bettcher and Heidi J. Chial

The research team appreciates the funding support by the University of Colorado Department of Neurology, the State of Colorado, the National Institutes of Health, the Alzheimer’s Association, and private philanthropists, including the Global Down Syndrome Foundation.

About the University of Colorado Anschutz


The University of Colorado Anschutz is a world-class academic medical campus leading transformative advances in science, medicine, education and patient care. The campus includes the University of Colorado’s health professional schools, more than 60 centers and institutes, and two nationally ranked independent hospitals - UCHealth University of Colorado Hospital and Children's Hospital Colorado - which see nearly three million adult and pediatric patient visits each year. Innovative, interconnected and highly collaborative, CU Anschutz delivers life-changing treatments, exceptional patient care and top-tier professional training. The campus conducts world-renowned research supported by $890 million in funding, including $762 million in sponsored awards and $128 million in philanthropic gifts for research.

 

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