This Program is a multidisciplinary effort dedicated to the study of Alzheimer's Disease (AD). This Project will be composed of three Cores and nine Individual Research Projects. An Administrative Core will be responsible for overseeing all aspects of the projects, budgetary matters and scheduling of all activities. A Clinical Core will be responsible for following established and the recruitment of new patient in the previous granting period and to continue physostigmine treatment in some of these individuals. Three new populations are to be recruited for newly planned studies, they include: a) AD patients with specific types of SPECT scans, b) AD patients with concurrent depressions, and c) Black AD patients and their families. DAta management and analysis will also be performed through this Core. A Tissue Procurement, Immunocytochemistry Core will be responsible for making pathological diagnosis, providing tissue for individual investigations, and performing immunocytochemical procedures. The Individual Research Projects are divided into Clinical and Basic Science proposals, with the former dedicated to the study of "Special Populations of AD Patient" (Project 1-3) and the latter to the "Cytoskeleton and Its Relationship to Metabolism" (Projects 4-9). Project 1 will investigate in the AD patient with depression the effect of treating the depression on functioning and quality of life. Project 2 will assess AD caregiver issues in black versus white families. Project 3 will investigate the biochemistry of the tau-paired helical filament cores and attempt to identify tau binding proteins in AD. Project 4 will provide a complementary approach to Project 3, by assessing qualitative changes in the CNS of AD by utilizing immunocytochemical (antibodies to tau and ALZ50) techniques. Project 5 will assess morphological changes in the aging rat hippocampus and correlate such changes with related alteration in the ultrastruction and biochemistry of microtubules. Project 6 will be a complementary approach to that of Project 5, by identifying the role of phosphorylation in altering the susceptibility of microtubule associated proteins (MAP-2, tau) to proteolysis by calpain and in modulating the binding properties of MAPS and identifying changes in these processes in the aging rat. Project 7 will identify regulators and modulators of choline release from phospholipids. Project 8 will study the impact of neuronal reorganizations on CNS functional integrity by assessing their effects of phosphoinositol metabolism.