The candidate is an MD trained clinical neurologist whose career goal is to investigate the pathophysiologic causes of Alzheimer's disease, with emphasis on studying Amyloid-Beta metabolism in humans. The proposed period of mentored scientific training in the laboratory of Dr. David Holtzman and clinical research training with Dr. John Morris at Washington University will allow the candidate to develop the skills necessary to become an independent investigator. The central hypotheses that will be tested during the proposed project are as follows: 1) Alzheimer's disease is associated with increased synthesis and/or decreased clearance of the amyloid- beta peptide (A?) in humans. 2) The risk factor of increased age is associated with increased synthesis and/or decreased clearance of A? in humans. 3) The risk factor of ApoE4 genotype is associated with decreased clearance of A? in humans. The candidate proposes to test these hypotheses using a recently developed method to measure the synthesis and clearance rate of A? in vivo in humans. Participants from the Washington University Alzheimer's Disease Research Center (ADRC) will be enrolled in the above studies to compare groups of 1) AD versus non-demented controls, 2) older age, middle age, vs. younger age, and 3) ApoE4 positive vs. ApoE4 negative. A detectable change in A? metabolism in humans that is associated with AD may ultimately lead to better diagnostic and therapeutic options. ? ? ?
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