We quantified the synaptic population density in the frontal cortex of 25 individuals without dementia 16 to 98 years old, using sections double-immunolabeled for β/A4 amyloid and for synaptophysin, and found a significant inverse correlation between the presynaptic terminal (PT) counts and age (r = −0.7, p < 0.001). Individuals older than 60 years had an average 20% decrease in PT density compared with individuals younger than 60 years. There were no significant correlations between the age and the number of (β/A4 amyloid-positive plaques or between synaptic density and the number of amyloid plaques. Further analysis of the digitized serial optical images showed focal areas of synapse loss and distended synaptophysin-containing boutons in the mature plaques of the normal aged cases. However, we found no microscopic changes in the synaptic content inside and outside the diffuse plaques. We suggest that a loss of synaptic input in the neocortex is an age-dependent factor that contributes to the overall synaptic loss in Alzheimer's disease, but that this might be largely independent of the (β/A4-amyloid deposition.