Synaptic pathology in prefrontal cortex is present only with severe dementia in Alzheimer disease

Synaptic pathology is proposed to be integral to the clinical expression of Alzheimer disease (AD). Most studies have assessed only the vesicle protei n synaptophysin as a measure of synaptic integrity. The interrelationships of synaptophysin, other presynaptic proteins, the cholinergic system, and s everity of dementia in AD remain unclear. We studied the presynaptic protei ns synaptophysin, syntaxin and SNAP-25, along with choline acetyltransferas e (ChAT) activity in prefrontal cortex (BA 46) samples from 18 subjects wit h AD and 16 controls. Mean values of presynaptic protein immunoreactivities were significantly reduced, by 21%-28%, and ChAT activity was reduced by 4 1% in the AD groups. Synaptic protein immunoreactivity and ChAT activity we re correlated with Mini-Mental State Examination scores obtained I yr prior to death. When AD cases were subgrouped into mild/moderate and severe illn ess at time of death, all differences in presynaptic proteins and ChAT acti vity were significant between controls and severe cases. However, no signif icant differences were detected in BA 46 between controls and mild/moderate cases. Considerable synaptic reserve or plasticity remains in BA 46 until the late stages of AD. Synaptophysin and ChAT appear to be more vulnerable in severe AD than are syntaxin or SNAP-25.