Down's syndrome (DS) is a genetic disorder caused by a triplication of chromosome 21 (chr21); it results in learning disabilities. It is recognised that many people with DS develop Alzheimer neuropathology by the 4thdecade of life. Synapse loss is one of the main pathological findings in the brain of subjects with AD and is an important correlate of cognitive decline, it may be detected by the assessment of key synaptic proteins levels in the post-mortem brain. This study assesses the levels of synaptic proteins in DS cases within the range 10–70 years of age. Post-mortem tissue has been used from a maximum of 90 DS subjects. Three synaptic proteins, β-tubulin, synaptophysin and PSD95, were assessed in the hippocampus, frontal and temporal cortices by western blotting. There was a signifcant decline in β-tubulin in the frontal cortex (Rs= -0.24, n= 86, p= 0.26) and temporal cortex (Rs= -0.37, n= 78, p= 0.001) in respect to age. Synaptophysin also significantly declined with age but only in the temporal cortex (Rs= -0.33, n= 78, p= 0.004). PSD95 did not show a change with age in any region. The present study demonstrates that there a decline in the neuronal marker β-tubulin in frontal and temporal cortices and in synaptophysin in temporal cortex as a function of age. The lack of change in the postsynaptic protein, PSD95, indicates perhaps that presynaptic terminals are more vulnerable than postsynaptic. Further studies will relate concentrations of synaptic proteins to quantitative and qualitative neuropathological markers of Alzheimer's disease.