Gelsolin plays an important role in the fibrillogenesis of amyloid-β (Aβ). It binds to Aβ and inhibits its fibrillization. Gelsolin also gets proteolytically cleaved under apoptotic conditions. We recently reported a correlation between proteolytic product of gelsolin (carboxyl-terminal fragment of gelsolin, gelsolin-CTF) and severity of Alzheimer's disease. In this study, we report that gelsolin is cleaved in the brains of adult individuals (age, 43-63 years) with Down syndrome (DS), and that levels of gelsolin-CTF are significantly increased in the frontal cortex of adult DS subjects as compared to age-matched control subjects. Gelsolin-CTF was not observed in frontal cortex of young DS (age 0.5-23 years) and age-matched control subjects. In addition, the levels of both soluble and total Aβ40 and Aβ42 were significantly increased in the frontal cortex of adult DS patients as compared to age-matched control subjects. A positive relationship was observed between gelsolin-CTF in frontal cortex of DS, and the levels of soluble Aβ40 (r2= 0.7820, p < 0.01) and Aβ42 (r2 = 0.8179, p < 0.01). Experiments with recombinant full-length gelsolin and its N-terminal and C-terminal fragments showed that similar to gelsolin, proteolytic fragments of gelsolin can also interact with soluble synthetic Aβ. The post-translational modification of gelsolin proteins may not be essential as these proteins (overexpressed in Escherichia coli) were able to form complexes with Aβ. These results suggest that there may be a relationship between proteolytic cleavage of gelsolin and increased Aβ in the brain. Since soluble non-fibrillar forms of Aβ are neurotoxic, they may be involved in apoptosis and proteolysis of gelsolin.