Neurotrophic agents may exacerbate the pathologic cascade of Alzheimer's disease

The thesis is advanced that Alzheimer's disease is triggered by alterations in the regulatory mechanisms governing the patterns of cytoskeletal protein expression in structurally plastic neurons in the mature nervous system. As a consequence, polypeptide species acting to stabilize the cytoskeleton are preferentially affected, and neuronal architecture becomes increasingly determined by proteins involved in labile structural states. A cascade of interdigitating pathologies is then postulated to develop characterized by nerve terminal aberrancies, subsequent extrusion of atypical polypeptide species and their conjugates, reactive gliosis, abnormal neuronal growth, and degeneration. Within this context, growth factors promote and accelerate the pathologic cascade. Based on this model, a treatment strategy is suggested that the most effective management of Alzheimer's disease, particularly during earlier stages, is to delay its projected normal onset and to control the aberrant neuronal growth that is a hallmark of the malady.