Previous research by our group and others has demonstrated that AD patients have mildly elevated levels of plasma cortisol, that approximately 40-50% of patients do not suppress cortisol secretion normally following dexamethasone administration, and that some AD patients have blunted cortisol responses to challenges with either TRH or CRF. These abnormalities are generally correlated with the extent of behavioral impairment. Numerous animal studies indicate that chronic elevation of corticosteroids may lead to neuron loss particularly in the hippocampus and that damage to the hippocampus, in turn, can lead to disinhibition of the HPA axis. We propose to determine whether any of the observed HPA axis abnormalities observed in AD patients are related to clinically significant differences in symptom progression over time, and whether HPA axis abnormalities are associated with the loss of neurotransmitter markers or cells in the hippocampus of patients who come to autopsy. During the next five years we will collect baseline HPA axis data, perform dexamethasone suppression tests, and give CRF infusions to at least 40 mild to moderately demented AD patients at baseline and yearly for at least 2 years. Changes in HPA axis measures will be correlated with changes in AD symptomatology measured by the Alzheimer's Disease Assessment Scale. In addition we will perform these same HPA axis tests on a group of at least 30 AD patients with advanced disease who are residing in extended care facilities with high autopsy rates. Autopsies will be performed on patients in either group who die during the next five years to determine loss of neurotransmitter markers and hippocampal cells.
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