Significant progress has been made in refining diagnostic criteria for AD and in developing imaging approaches to exclude treatable disease and to assess some of the metabolic processes occurring in vivo in the brains of individuals with AD. However, as yet, no reliable diagnostic test is available. Although risk factors have been identified, the etiology of AD remains an enigma. The roles of familial, chromosomal, and genetic factors, toxins, and transmissible agents in the pathogenesis of this disease deserve intensive study. A variety of neurotransmitter systems are affected in the disease, and it seems likely that new approaches may identify additional systems at risk. Of particular importance will be studies on surviving neurons, since these cells will be targets for treatment. Neurons in certain parts of the brainstem, basal forebrain, amygdala, hippocampus, and neocortex show several types of cytoskeletal abnormalities, but mechanisms of cytoskeletal disorganization are not well understood, e.g. we do not have a clear idea of the sequence of cytoskeletal pathology, the time course of dysfunction of individual neurons, and consequences of these processes on cell function. In situ hybridization with radiolabeled nucleic acid probes and immunocytochemical approaches should provide information about levels of gene expression, protein compositions, and posttranslational modifications of normal and abnormal proteins in these cells. The relationships and sources of some of the abnormal proteins (e.g. those associated with PHF, 15-nm straight filaments, plaque amyloid, and vascular amyloid) can be clarified by new approaches of protein chemistry (purification and sequencing) and molecular biology (recombinant DNA techniques). Finally, investigations of animal models that recapitulate certain features of AD should provide new insights into the nature, mechanisms, and consequences of cellular pathology of specific systems. These models may be useful for imaging studies similar to those used in human patients and for developing and testing new therapeutic approaches that eventually may be useful for treating this all-too-common disorder of the central nervous system.