The coupling of cortical muscarinic receptors to guanosine triphosphate (GTP) binding proteins, as defined by changes in agonist affinity states of the receptor in the presence of magnesium ions (Mg2+) and a GTP analogue has been investigated using carbachol in competition experiments with either N-methylscopolamine (NMS) or pirenzepine (PZ). The stability of the system with regard to autopsy delay and freezing was first established in membrane preparations from mouse brain. Applying the same methods to human autopsy tissue from the parietal cortex of Alzheimer's diseased cases and controls, matched for age and postmortem delay, there was no significant difference in the detectable coupling of the total (NMS-labelled) muscarinic receptor population. However, coupling of the 'M1' muscarinic receptor subtype, selectively labelled by PZ, appeared to be more labile than that of the receptor population as a whole and the modulation of this subtype by the GTP analogue was significantly attenuated in Alzheimer's disease.