Background One of the most characteristic changes in Alzheimer’s disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes. Objective To investigate differences in the distribution of M1/M4 receptors using (R, R) 123 I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and age-matched controls. Also, to compare I-123-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects. Methods Forty two subjects (18 AD and 24 healthy elderly controls) underwent I-123- QNB and perfusion Tc-99m-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively. Results Significant reductions in I-123-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p <= 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables. Conclusion Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.