Applying the relatively new technique of laser confocal imaging, vibratome sections which were double immunolabeled for amyloid beta protein and the presynaptic terminal marker synaptophysin were examined. It was found that while synaptic density was generally diminished in Alzheimer's disease (AD) cortical neuropil as compared to controls, the reduction was no greater within the diffuse plaques than outside them. Synapse loss was accentuated, however, within immature and mature plaques. These findings suggest that the pathogenetic process in AD might commence with synapse loss and neurodegeneration rather than with deposition of amyloid beta protein.