The efficacy of acetylcholine muscarinic M2 receptor-G-protein coupling was investigated in Alzheimer's disease and control neocortical membranes by measuring the effects of MgCl 2 and 5 -guanylylimidodiphosphate (Gpp[NH]p) on high-affinity [ 3 H]oxotremorine-M ([ 3 H]OXO-M) binding. MgCl 2 gave similar enhancements of [ 3 H]OXO-M binding in Alzheimer's disease and control occipital cortex. In contrast, MgCl 2 enhanced [ 3 H]OXO-M binding was significantly higher in Alzheimer's disease superior temporal cortex, compared to controls. MgCl 2 enhanced [ 3 H]OXO-M binding in both the occipital and temporal cortices of the Alzheimer's disease cases was reversed to control levels by Gpp[NH]p. It is concluded that the number of high-affinity muscarinic M2 sites is increased in Alzheimer's disease superior temporal, but not occipital, cortex and that M2 sites in both regions maintain an efficient G-protein coupling.