Aggregated amyloid beta-protein (A beta) is a key component of the amyloid depositions found in the brains of patients with Alzheimer's disease. In contrast, in cerebrospinal fluid (CSF), A beta is found in a soluble form. The analysis of complexes of A beta with CSF proteins in a KBr gradient revealed an association of A beta only with free proteins and not with lipoprotein particles. Transthyretin (TTR), a second major CSF protein, formed SDS-stable complexes with A beta and significantly decreased the rate of A beta fibril formation. In physiological buffers and CSF, TTR exclusively decreased the level of A beta pentamers. Endogenous TTR-A beta complexes were detected in human CSF by immunoprecipitation. Using site-directed mutagenesis and computer-assisted modelling, we identified amino acid residues on the surface of the TTR monomer that interact with A beta. Specific TTR immunoreactivity was detected in multiple cortical neurons and astrocytes in the human brain. We propose that A beta binding proteins play a key role in the modulation of A beta aggregation and normally prevent amyloid formation in biological fluids and in the brain.