The objective of our research was to determine synaptic protein levels in brain specimens from AD subjects and agematched control subjects. Further, to determine whether presynaptic or postsynaptic compartments of neurons are preferentially affected in AD patients, we studied 3 presynaptic vesicle proteins (synaptotagmin, synaptophysin, and Rab 3A), 2 synaptic membrane proteins (Gap 43 and synaptobrevin), and 2 postsynaptic proteins (neurogranin and synaptopodin) in specimens from AD and age-matched control brains. Two brain regions -the frontal and parietal cortices -were assessed for protein levels by immunoblotting analysis. We found a loss of both presynaptic vesicle proteins and postsynaptic proteins in all brain specimens from AD patients compared to those from age-matched control subjects. Further, we found that the loss of synaptic proteins was more severe in the frontal cortex brain specimens than in the parietal cortex brain specimens from the AD subjects compared to those from the control subjects, suggesting that the frontal brain may be critical for synaptic function in AD. Using immunohistochemistry techniques, we also determined the distribution pattern of all synaptic proteins in both the frontal and parietal cortices brain specimens from control subjects. Of the 7 synaptic proteins studied, the presynaptic proteins synaptophysin and rab 3A and the postsynaptic protein synaptopodin were the most down-regulated. Our study suggests that postsynaptic proteins and presynaptic proteins are important for synaptic function and may be related to cognitive impairments in AD.