Blood measure of neuronal death is exponentially higher with age, especially in females, and halted in Alzheimer’s disease by GM-CSF treatment

Aging increases the risk of neurodegeneration, cognitive decline, and Alzheimer's disease (AD). We report that plasma concentrations of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and neurofilament light (NfL) become exponentially higher from ages 2 to 85 in cross-sectional samples, serving as neuronal death/damage biomarkers across the lifespan. UCH-L1 concentrations rise faster in females, who exhibit increased AD risk. Glial fibrillary acidic protein (GFAP) concentrations increase exponentially after age 40, especially in females. Age-adjusted UCH-L1, NfL, and GFAP plasma concentrations are greatly elevated in mildly cognitively impaired participants. Treatment of human AD trial participants with granulocyte-macrophage colony-stimulating factor (GM-CSF/sargramostim) apparently halts neuronal cell death: UCH-L1 biomarker concentrations are reduced to those of 5-year-old healthy controls. GM-CSF treatment also reduces neuronal apoptosis and astrogliosis in a rat model of AD. An exponential increase in neurodegeneration with age, accelerated by astrogliosis/inflammation, may underlie the contribution of aging to cognitive decline and AD and can be halted by GM-CSF/sargramostim treatment.