Aims: This study quantified the density of the synaptic proteins synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in brains from elderly Down's syndrome individuals. Methods: Six areas (frontal, occipital, parietal and temporal lobes, cerebellum and hippocampus) of post mortem brains from elderly Down's syndrome (DS) individuals (with reported functional memory problems and pathologically established Alzheimer's disease) and elderly controls were studied. Results: Collectively in the six brain areas studied, there were significantly lower levels of both synaptophysin and SNAP-25 immunostaining in the DS group compared with controls. The elderly control group displayed a significant decrease in the densities of synaptophysin and SNAP-25 as a function of age at death (AAD; P ≤ 0.001), whereas the DS group only showed a significant decrease as a function of AAD for synaptophysin. Assessing synaptic density as a function of Braak stage (BST) revealed a significant decrease in synaptophysin density for both groups. SNAP-25 was only significantly decreased as a function of BST in the DS group. Synaptic protein density was also shown to vary according to gender. Thus, both DS and control female subjects had a higher synaptic density of SNAP-25 than their male counterparts. In contrast, male DS and control individuals had a significantly greater density of synaptophysin than females. Conclusions: These results indicate that elderly DS individuals have lower synaptic densities of both analysed proteins than cognitively intact elderly individuals. Although AAD and BST show varying significance to decreases in protein density for both DS and control groups, results suggest that gender differences also play a role in the type of synaptic protein lost in elderly DS individuals.