Quantitative assessment of cortical synaptic density in Alzheimer's disease

Significant progress has been made over the last decade in delineating the neuropathological and neurochemical changes in the brains of patients with Alzheimer's disease (AD). Less well studied are the actual synaptic connections of affected areas of the brain, such as the cerebral cortex. Because the final common pathway for neurotransmission involves synaptic integrity, we quantitatively assessed synaptic number and synapse size in lamina III and V of human frontal cortex (Brodmann area 9) in patients with AD and age-matched controls. Samples were also matched for postmortem interval, and artifacts associated with postmortem change were eliminated. We found a significant decrease in synaptic number per unit volume in both lamina, more marked in lamina III (-42%) than V (-29%). In both normal controls and AD brains, there was a negative correlation between synapse number and synapse size as indexed by the length of the postsynaptic density (PSD); cortical samples with fewer synapses had larger synapse size. This appeared to be a compensatory response, rather than a selective loss of small synapses, since the total amount of synaptic contact area per unit volume did not decline in lamina V (despite a 29% loss of synapses); in lamina III it was reduced 11% despite a 42% loss of synapses. The loss of synapses in AD is widespread and significant in frontal cortex; there is observable compensation by enlargement of synaptic size. This compensatory effort is overcome by the continuing loss of synapses in areas most affected by the degeneration.