The primary causes of cognitive impairment in Alzheimer's disease (AD) are not known with certainty. New therapeutic strategies are being developed for the normal elderly population (many of whom have pre-symptomatic AD changes in brain) and those with the earliest cognitive changes, known as MCI (mild cognitive impairment). Such impaired cognition represents the behavioral manifestation of specific pathologies and as-yet-unknown combinations of structural (e.g., synaptic and neuron loss or dysfunction) and biochemical changes (notably neurotransmitter changes, especially cholinergic). In this regard, we confirmed and extended recent findings indicating that choline acetyltransferase (ChAT) activity is stable in people with MCI or even mild AD. In addition, we found that ChAT levels are elevated in hippocampus in MCI. We ascribe this hippocampal biochemical change to sprouting of the cholinergic source neurons in response to partial denervation of the hippocampal dentate gyrus, due to the loss of entorhinal cortex layer 2 hippocampal projection neurons in MCI. Interestingly, we also observed a decrease in acetylcholinesterase (AChE) activity, the degrading enzyme for acetylcholine, in both the hippocampus and frontal cortex in MCI and AD. The present proposal seeks to determine the structural and biochemical changes underlying our novel hippocampal plasticity response in people with MCI. We will assess members of the Religious Orders Study who have MCI, compared to cognitively normal (NCI) and mild AD cases in the same cohort. Using ultrastructural techniques, we will perform synapse counts in the hippocampus, superior frontal and inferior temporal cortex. We will assess ChAT and (AChE) activity in these same regions, with special attention to the transition from NCI (with or without AD pathological changes), to MCI (whose AD pathology may range from mild to more marked) to frank AD. In collaboration with Dr. Mufson (Project 3) we will correlate these changes with: alteration of ChAT, trkA and p75-NTR in the cholinergic neurons of the medial septum and diagonal band of Broca (MS/DB), the projection neurons to the hippocampus. These studies will define what changes, in addition to ERC cell pathology and hippocampal synapse loss, are associated with development of MCI and progression to AD. Understanding the status of synaptic connectivity in MCI brain will allow us to better determine the structural changes in MCI and devise effective pharmacotherapies.