The aged dog brain accumulates β-amyloid in the form of diffuse senile plaques, which provides a potentially useful in vivo model system for studying the events surrounding the deposition of β-amyloid. We used postembedding immunocytochemistry at the electron microscopic level to determine the subcellular distribution of β-amyloid 1-40 and β-amyloid 1-42 peptides in the prefrontal and parietal cortex of behaviorally characterized dogs ranging in age from one to 17 years. Immunogold particles signaling β-amyloid 1-42 occurred over intracellular and extracellular fibrils that were approximately 8nm in width. Intracellular β-amyloid 1-42 fibrils were found in close proximity to glial fibrillary acidic protein fibers within astrocytes, but only in cells with signs of plasma membrane disruption. Neuronal labeling of β-amyloid 1-42 appears to be associated with the plasma membrane. Membrane-bound β-amyloid 1-42 occurs in the form of fine fibrils that are embedded in the dendritic membrane and appear to project into the extracellular space as determined by quantitative analysis of the immunogold particle distribution. Bundles of β-amyloid 1-42 were also closely associated and/or integrated with degenerating myelin sheaths of axons. In one dog that was impaired on several cognitive tasks, extensive β-amyloid 1-42 deposition was associated with microvacuolar changes and vascular pathology. The present findings suggest that β-amyloid 1-42 may be generated at the dendritic plasma membrane as well as in intracellular compartments. The close association between β-amyloid 1-42 and destroyed myelin suggests one possible new mechanism by which β-amyloid 1-42 induces neurodegeneration.