The deposition of fibrillar amyloid beta-protein (Aβ) is one of the main events in the amyloid plaques formation in Alzheimer's disease (AD) and adult Down syndrome (DS) individuals. Accumulating evidence from our and other groups has shown that gelsolin, a cytoplasmic and secretory protein, regulates the fibrillogenesis of Aβ. Gelsolin is constitutively expressed through out the central nervous system, and it inhibits the fibrillization of Aβ, and defibrillizes the preformed Aβ fibrils. We studied whether there is a relationship between the levels of Aβ and gelsolin in the brains of AD and DS subjects. The homogenates of postmortem brain samples of frontal cortex from patients with AD (age 64-85 y, n = 8) and DS (age 43-63 y) and age-matched control subjects were prepared. Then homogenates were analyzed for gelsolin and its proteolytic fragment by Western blot. The levels of Aβ were measured in the homogenates by ELISA.. Our results showed the presence of a carboxyl-terminal gelsolin peptide (CTF-gelsolin), a proteolytically cleaved fragment of gelsolin, in the brain sample from AD but not in age-matched controls (n = 6). A correlation was observed between the levels of CTF-gelsolin and severity of the disease. Similarly, we observed that proteolysis of gelsolin also occurs in the brains of adult DS (n = 7) but not in age-matched control (n = 6) subjects. The levels of soluble Aβ40/Aβ42 were increased in the brains of adult patients with DS. A positive correlation was observed between the levels of soluble Aβ40/Aβ 42, and the proteolysis of gelsolin. We suggest that gelsolin cleavage in the brains may act as a marker of amyloid -mediated pathogenesis in AD and DS.