Scientists at the University of Colorado Anschutz have found that changes in brain neurons, including gradual cell loss, may begin much earlier in life than previously thought. Their research also suggests that a drug already approved for other medical uses could potentially be repurposed to slow this damage, offering fresh hope for people living with Alzheimer’s disease and other cognitive disorders. The findings highlight a possible new direction in tackling neurodegeneration, an area where effective treatments remain limited.
The study, published in Cell Reports Medicine, builds on earlier clinical work involving sargramostim, also known as Leukine. According to senior author Professor Huntington Potter, director of the University of Colorado Alzheimer’s and Cognition Center, the drug showed encouraging effects in its first clinical trial. Over a relatively short period, sargramostim reduced a blood-based marker of neuron death in people with Alzheimer’s disease and improved performance on one established cognitive test. These findings are notable because they link biological evidence of reduced neuronal damage with measurable cognitive benefit.
Sargramostim is a synthetic version of GM-CSF, a natural human protein that stimulates the immune system. It has been used safely for around 30 years, particularly in cancer care, to promote the production of immune cells. In early neurological studies, the drug improved blood biomarkers associated with brain pathology. While these biomarker improvements were only maintained during active treatment, gains in one measure of memory persisted beyond the treatment period, suggesting longer-lasting effects on brain function.
In the new cross-sectional study, researchers examined blood samples from individuals across a wide age range. They focused on proteins released when neurons are damaged or die, including UCH-L1 and neurofilament light chain (NfL). Levels of both proteins were low in early life but increased exponentially with age, reaching much higher concentrations in later adulthood. While modest increases earlier in life likely reflect normal ageing, higher levels in older age were associated with poorer outcomes, pointing to accelerated neuronal damage as a contributor to cognitive decline and Alzheimer’s disease.
The team also measured glial fibrillary acidic protein (GFAP), a marker of brain inflammation believed to play a central role in cognitive deterioration. GFAP levels rose significantly from around age 40, supporting the idea that neuroinflammation intensifies in midlife and may drive later neuronal loss. Interestingly, age-related levels of GFAP and UCH-L1 were higher in women than in men, although the reasons for this difference remain unclear.
Results from the clinical trial were particularly striking. People with Alzheimer’s disease who received sargramostim showed a roughly 40 per cent reduction in blood levels of UCH-L1, comparable to levels typically seen much earlier in life. They also performed better on the Mini-Mental State Examination than those receiving a placebo. Although UCH-L1 levels returned to pre-treatment values after the drug was stopped, the cognitive improvement persisted, raising essential questions about how the treatment works and how long its benefits might last.
The authors caution that these findings are still preliminary. Blood markers of neuronal damage change naturally with age, and more research is needed to determine whether sargramostim can slow normal age-related cognitive decline or requires continuous use to maintain its effects. A larger, longer clinical trial in people with mild-to-moderate Alzheimer’s disease is currently underway. Until regulatory review is complete, the drug should not be used outside its approved indications.
More information: Stefan H. Sillau et al, Blood measure of neuronal death is exponentially higher with age, especially in females, and halted in Alzheimer’s disease by GM-CSF treatment, Cell Reports Medicine. DOI: 10.1016/j.xcrm.2025.102525
Journal information: Cell Reports Medicine Provided by University of Colorado Anschutz
