Abstract: We have recently reported evidence that a very high affinity interaction between the β-amyloid peptide Aβ1-42 and the α7 nicotinic acetylcholine receptor (α7nAChR) may be a precipitating event in the formation of amyloid plaques in Alzheimer's disease. In the present study, the kinetics for the binding of Aβ1-42 to α7nAChR and α4β2nAChR were determined using the subtype-selective nicotinic receptor ligands [3H]methyllycaconitine and [3H]cytisine. Synaptic membranes prepared from rat and guinea pig cerebral cortex and hippocampus were used as the source of receptors. Aβ1-42 bound to the α7nAChR with exceptionally high affinity, as indicated by Ki values of 4.1 and 5.0 pM for rat and guinea pig receptors, respectively. When compared with the α7nAChR, the affinity of Aβ1-42 for the α4β2nAChR was ∼5,000-fold lower, as indicated by corresponding Ki values of 30 and 23nM. The results of this study support the concept that an exceptionally high affinity interaction between Aβ1-42 and α7nAChR could serve as a precipitating factor in the formation of amyloid plaques and thereby contribute to the selective degeneration of cholinergic neurons that originate in the basal forebrain and project to the cortex and hippocampus.