Alzheimer's disease entails multiple neuronal systems and results from neuronal cytoskeletal degeneration of only a few types of nerve cells. Essential for neuropathological diagnosis is assessment of the presence of neurofibrillary tangles and neuropil threads. The destructive process begins in predisposed cortical induction sites, thereafter invading other portions of the cerebral cortex and specific sets of subcortical nuclei in a predictable sequence with little variation. The location of the tangle-bearing neurons and severity of the pathology allow the distinction of six stages in disease propagation (transentorhinal I-II: clinically silent cases; limbic III-IV: incipient Alzheimer's disease; neocortical V-VI: fully-developed Alzheimer's disease). The pattern of appearance of the neurofibrillary changes bears a striking resemblance to the inverse sequence of cortical myelination. The average myelin content is a negative image of the density of intraneuronal lipofuscin deposits. Pigment-laden neurons endowed with a long, thin, and sparsely myelinated axon are prone to develop AD-related changes. The emergence of the first neurofibrillary changes, at whatever age these occur, signals the onset of a degenerative process that persists until death. An extended period of time elapses between the beginning of histologically verifiable lesions and the appearance of initial clinical symptoms. Once initiated, however, cytoskeletal deterioration inexorably progresses, and neither remission nor recovery is observed.