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, Ph.D., director of the University of Colorado Alzheimer's
and Cognition Center at CU Anschutz.
Drug background and trial results
The drug, sargramostim (also called Leukine), 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, Ph.D., Christina Coughlan, Ph.D. and Md. Mahiuddin Ahmed, Ph.D., 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.
Biomarker findings and gender differences
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.
How sargramostim may work
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.
Unanswered questions and next steps
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
Source: Natural protein drug may slow neuron death linked to Alzheimer's disease
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