Cognitive impairment in the elderly is a major health, social and economic problem affecting about 15% of the population over age 65. Over half of these cases are due to dementia of the Alzheimer's type (DAT). This proposal focuses on the diagonal band of Broca (DB), a part of the basal forebrain projection system known to be prominently involved in Alzheimer's disease, and asks two basic questions: (1) what is the anatomical organization of the DB which may predispose it to Alzheimer's pathology? (2) what specific changes occur in the DB and how do they contribute to the pathogenesis of Alzheimer's disease? The question of a causal relationship between cortical pathology and basal forebrain degeneration in DAT needs to be resolved. The DB provides cholinergic innervation to specific brain regions which consistently show marked pathology and cholinergic deficit in DAT. This work will use quantitative autoradiography, histochemistry, morphometry, Golgi impregnation and electron microscopy to study DB changes in DAT. Combined methods will be used to determine the role of human DB neurons in the pathogenesis of neuritic plaques and neurofibrillary tangles. Studies of the normal cellular structure, neurotransmitter content and connectivity of the DB will be extended to test the hypothesis that the organization of the DB resembles the reticular formation and provides widespread innervation of limbic structures. Combined techniques will be applied to determine if parallel cholinergic and GABAergic projection systems are a consistent feature in the DB, to elucidate the nature of an intrinsic DB network and to characterize synaptic input fat the ultrastructural level. Results of this work will provide a more clear understanding of the anatomical organization of the basal forebrain, insight into the vulnerability of the basal forebrain cholinergic system and evidence for the mechanism of cellular injury in Alzheimer's disease.