Basic Science and Pathogenesis

Increasing age is the greatest risk factor for developing Alzheimer's disease (AD) and of 'normal' cognitive decline. People with Down syndrome/trisomy 21 (DS) have cognitive challenges throughout life and have a near 100% risk of developing AD neuropathology by age 40, with most developing AD dementia by age 60. We showed in a cross-sectional study of community dwelling normosomic individuals that plasma concentrations of UCH-L1 and NfL, measures of the rate of neuronal cell loss/apoptosis and axon damage, respectively, show exponential increases with age starting in early childhood. Plasma concentrations of GFAP, a marker of astrogliosis/inflammation, increase exponentially starting at around age 40. We also showed that the immune system modulating cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) improved cognition and reduced neuronal apoptosis in animal models of aging, AD, and DS, and that treatment of AD participants with human recombinant GM-CSF/sargramostim in a phase II trial improved a measure of cognition, reduced plasma UCH-L1, and partly normalized plasma Ab40 and total Tau (PMID:39072024).

Plasma concentrations of UCH-L1, NfL, and GFAP were assessed in 316 individuals with DS age 2-60 using the Quanterix SIMOA^Ò platform and compared to previous findings from normosomic, healthy, age-matched controls. Neuronal apoptosis in the Dp16 mouse model of DS was assessed by Caspase-3 staining.

Plasma concentrations of biomarkers of ongoing neuronal damage (UCH-L1 and NfL) and gliosis/inflammation (GFAP) in the brain are significantly increased in individuals with DS starting in childhood, and their exponential increase with age occurs at a much faster rate than in normosomic individuals. Preliminary measures of neuronal apoptosis and gliosis are also increased in the brains of Dp16 mice.

Age-associated increases in plasma measures of the rate of neuronal death/damage and astrogliosis/inflammation in people with DS compared to normosomic individuals and of neuronal apoptosis in a mouse model of DS indicate an accelerated rate of brain aging, likely caused by increased APP expression and consequent production of neurotoxic Ab and exacerbated by astrogliosis/inflammation. Clinical trials are indicated for testing whether GM-CSF (sargramostim) treatment may reduce neuronal death/damage and gliosis and improve cognition in young adults with DS and in typical normosomic aging individuals.