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Adults with probable Alzheimer' Disease (AD) without the apolipoprotein E (APOE) E 4 allele demonstrate insulin resistance and reduced insulin concentrations in cerebrospinal fluid (CSF). Such findings may be of critical relevance to the study of AD, given growing evidence that insulin plays a role in hippocampal and other brain functions. Recent studies have also linked insulin to key pathophysiologic processes such as metabolism of the amyloid precursor protein (APP) and beta-amyloid (Abeta), a primary constituent of senile plaques. Increasing plasma insulin lowers plasma APP levels for normal adults, but raises APP levels for patients with AD without an APOE-E allele. Furthermore, the metalloprotease insulin degrading enzyme plays a primary role in Abeta degradation. The proposed studies will test the hypothesis that raising plasma insulin increases CSF levels of APP and Abeta for patients with AD and for patients with Mild Cognitive Impairment (MCI), who are at risk for AD. The nature of these effects will be determined for Abeta42 and APPbeta which are believed to confer increased pathogenetic risk, compared with effects for Abeta40 and APPalpha. Normal adults, and adults with AD and MCI will receive saline and insulin infusions on separate days, following which lumbar puncture will be performed to obtain CSF for APP and Abeta analysis. Normal and MCI groups will return after 2 years for cognitive evaluation and for infusions with lumbar puncture, to test the hypothesis that defective insulin action and insulin-related changes in CSF levels of Abeta and other parameters predict cognitive decline for patients with MCI. A second study will examine the memory-enhancing effects of somatostatin, a neuropeptide that inhibits insulin secretion. In this study, normal, AD, and MCI subjects will receive infusions of saline, insulin, somatostatin, or insulin plus somatostatin, and memory performance will be compared across conditions. Confirmation of the hypotheses in the proposed studies will open several new research avenues, including identification of susceptibility genes that modulate insulin sensitivity in AD, and as well as suggesting new therapeutic approaches that enhance insulin sensitivity and reduce hyperinsulinemia.

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