Scientists at the University of Colorado Anschutz have found that a drug already approved for other medical conditions may help slow neuron loss in people with Alzheimer's disease. The research, published in Cell Reports Medicine, focused on sargramostim (also known as Leukine), which is a synthetic version of the human protein GM-CSF and has been used for decades to treat cancer and other diseases.
In their study, researchers examined blood samples from people across different ages. They measured proteins such as UCH-L1 and NfL, which are released into the blood when brain neurons die or are damaged. The team found that levels of these proteins remain low early in life but increase significantly with age, reaching much higher concentrations by age 85. Higher levels of UCH-L1 later in life were linked to worse outcomes, suggesting that these markers could be useful for earlier testing and development of new therapies for Alzheimer’s disease and cognitive decline associated with aging.
The researchers also observed that another protein, GFAP—which indicates brain inflammation—begins to rise in the blood starting around age 40. Both GFAP and UCH-L1 were found at higher levels in women compared to men, though the reasons for this difference are not yet understood.
"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," said Potter.
Potter explained that GM-CSF stimulates immune cell production in both bone marrow and brain while also affecting inflammation. In animal studies, "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."
Patients who received sargramostim also showed improved scores on one cognitive test—the Mini-Mental State Exam (MMSE)—compared to those given a placebo. Other tests did not show changes.
Researchers noted it is still unclear whether continuous use of sargramostim will be necessary to maintain its effects on neuron damage related to Alzheimer’s disease. Forty-five days after stopping treatment, UCH-L1 levels returned to pre-treatment values but improvement on the MMSE remained. Further research is needed to determine if sargramostim can reduce normal age-related neuron loss or cognitive decline.
The authors cautioned that these results are preliminary and that changes in blood neuronal markers occur naturally as part of aging. A larger clinical trial involving people with mild-to-moderate Alzheimer’s disease is currently underway. Until further research is completed and regulatory approval is granted by the FDA, they advised against using sargramostim for unapproved purposes.
The study was co-authored by Stefan Sillau, Christina Coughlan, Md. Mahiuddin Ahmed, 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.
Funding for this work came from several sources including the University of Colorado Department of Neurology; state support; national agencies such as the National Institutes of Health; organizations like the Alzheimer's Association; and private donors including those from the Global Down Syndrome Foundation.
