In Alzheimers disease (AD) there is a progressive cognitive deterioration which is far greater than that observed in normal aging. This decline is paralleled by neuropathological and neurochemical alterations and has been closely linked to a continuous decrement of large neurons and extensive synapse loss in the neocortex. Synaptic loss may well occur before the neuronal loss. In the young adult CNS, growth quiescent neurons manifest a reactive repair process in response to damage, leading to a replacement of lost synaptic contacts. Because the final common pathway for neurotransmission involves synaptic integrity, it is important to assess the extent of this compensatory response throughout aging. It is also important to understand the effect of the aging factor on synaptic loss in AD as wells its relationship to any age-related cell loss or shrinkage. The present studies will utilize ultrastructural techniques to evaluate the synaptic density in the neocortex and hippocampus throughout the adult human life span (20-95 yrs). These studies will test the hypothesis that there is an age-related decline in synaptic density in human neocortex and hippocampal formation which is beyond the normal compensatory mechanisms of the aging brain. This age-related decline in synaptic numbers is closely related to the age-dependent decline in larger teurons~either within the cortical area itself or in areas which have a direct projection to the region which manifests synapse loss.
Specific aim #1 will quantify and correlate the synaptic density and neuronal density in frontal and temporal neocortex throughout the human life span in cognitively normal subjects.
Specific aim #2 will quantify and correlate the synaptic density in the molecular layer of the hippocampal dentate gyrus and neuronal density in the entorhinal cortex throughout the life span in cognitively normal subjects. These studies will definitively answer whether there is an age-related decline in synapses and define the relationship to neuronal loss.
