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We have examined the relationships between dementia, loss of synaptic proteins, changes in the cytoskeleton, and deposition of beta-amyloid plaques in the neocortex in a clinicopathologically staged epidemiological cohort using a combination of biochemical and morphometric techniques. We report that loss of synaptic proteins is a late-stage phenomenon, occurring only at Braak stages 5 and 6, or at moderate to severe clinical grades of dementia. Loss of synaptic proteins was seen only after the emergence of the full spectrum of tau and beta-amyloid pathology in the neocortex at stage 4, but not in the presence of beta-amyloid plaques alone. Contrary to previous studies, we report increases in the levels of synaptophysin, syntaxin, and SNAP-25 at stage 3 and of alpha-synuclein and MAP2 at stage 4. Minimal and mild clinical grades of dementia were associated with either unchanged or elevated levels of synaptic proteins in the neocortex. Progressive aggregation of paired helical filament (PHF)-tau protein could be detected biochemically from stage 2 onwards, and this was earliest change relative to the normal aging background defined by Braak stage 1 that we were able to detect in the neocortex. These results are consistent with the possibility that failure of axonal transport associated with early aggregation of tau protein elicits a transient adaptive synaptic response to partial de-afferentation that may be mediated by trophic factors. This early abnormality in cytoskeletal function may contribute directly to the earliest clinically detectable stages of dementia.