Neuropathology of Alzheimer’s disease: what is new since A. Alzheimer?

Abstract

Alzheimer’s disease results from severe cytoskeletal alterations in only a few neuronal types within the human central nervous system. These intraneuronal changes take the form of neurofibrillary tangles and neuropil threads. Beginning in predisposed induction sites in the allocortex, the lesions follow a predictable sequence as they engulf other territories of the cerebral cortex and a specific set of subcortical nuclei. Some components of the brain are devastated, while others remain intact until the end phase of the disease. Assessment of the location of the afflicted neurons and the severity of the lesions allows the distinction of stages in the development of the disease. The degenerative process begins with the emergence of the first lesions, at whatever age it occurs. The illness remains subclinical for years, and proceeds inexorably, gradually laying waste to higher order limbic system centers. Clinical symptoms are observed only late in the course of the disease, and their appearance is usually concurrent with the encroachment of the destructive process upon neocortical association areas. The sequence of destruction bears a striking resemblance to the inverse sequence of cortical myelination. Late myelinating areas and layers develop the disease-related changes earlier and at higher densities than those which are myelinated early. The brain of the human adult is heavily laden with intraneuronal deposits of lipofuscin and neuromelanin pigment. The average density of neuronal pigmentation in given cortical areas mirrors the density of cytoskeletal lesions that develop in the course of the disease. Pigment-laden neuronal types giving rise to a single long, thin, unmyelinated or sparsely myelinated axon are particularly prone to developing Alzheimer’s disease-related cytoskeletal changes.