Certain neuron classes in the cerebral cortex exhibit heightened vulnerability in Alzheimer's Disease, whereas others are relatively resistant to pathology. For example quantitative neuroanatomic analyses suggest that large pyramidal cells that furnish long corticocortical projections and reside in layers III and V may be particularly vulnerable to degeneration and/or neurofibrillary tangle and neuritic plaque formation. The experiments outlined in this project are directed at the development of a detailed molecular/anatomic profile of these pyramidal neurons. In addition, investigation of the cellular pathology of cerebral cortex in other dementing illnesses will be initiated, in order to determine the degree to which other dementias can be traced to the loss of the same subset of cortical cells and connections, regardless of the etiology. A common neuroanatomic denominator for dementia would greatly facilitate attempts to understand the cellular basis of dementing illnesses, and in turn, aid in directing therapeutic and preventative efforts to the appropriate cell class. These studies will involve detailed quantitative neuroanatomic analyses of non-human primate as well as neurologically normal and diseased human cortices. The anatomic methods employed will be chemically-specific histochemical procedures that allow for the correlation between biochemical or molecular data and cellular localization. The biochemical systems to be investigated include, cytoskeletal proteins, calcium-binding proteins, amyloid-beta-protein, and the excitatory neurotransmitter glutamate. The quantitative neuroanatomic analyses rely on computer-assisted microscopy and involve studies of cell distribution as well as morphologic and intracellular characteristics of individual neurons. An important underlying assumption in this proposal is that the selective vulnerability in Alzheimer's Disease is related to the molecular and anatomic heterogeneity of the neuronal constituents of cortex, and that a specific anatomic/molecular profile renders a cell vulnerable. If the elements of the biochemical and anatomic phenotype that are most clearly linked to differential cellular vulnerability in AD can be determined then it will be possible to develop means to protect those neurons that degenerate in AD. The protection of these neurons must be the paramount goal in developing a strategy for the management of AD, since prevention of a neurodegenerative disease is much more likely to be achievable than the development of a cure.