Microscopically, there is widespread loss of nerve cells. Early in the disease this is most pronounced in layer II of the entorhinal cortex. In addition to marked neuronal loss in the hippocampus, adjacent parts of the medial temporal cortex—namely, the parahippocampal gyri and subiculum—are affected. The anterior nuclei of the thalamus, septal nuclei, and diagonal band of Broca, amygdala, and particular brainstem parts of the monoaminergic systems are also depleted. The cholinergic neurons of the nucleus basalis of Meynert (the substantia innominata) and locus ceruleus are also reduced in number, a finding that has aroused great interest because of its putative role of the former in memory function (see in the following text). In the cerebral cortex, the cell loss predominantly affects the large pyramidal neurons. Residual neurons are observed to have lost volume and ribonucleoprotein; their dendrites are diminished and crowd one another owing to the loss of synapses and neuropil. Astrocytic hypertrophy (more than proliferation) is in evidence as a compensatory or reparative process, most prominent in layers III and V.
Three additional microscopic changes give this disease its distinctive character: (1) The presence within the nerve cell cytoplasm of thick, fiber-like strands of silver-staining material, also in the form of loops, coils, or tangled masses (Alzheimer neurofibrillary changes or “tangles”) (Fig. 38-1). These strands are composed of a hyperphosphorylated form of the microtubular protein, tau, and appear as pairs of helical filaments when studied ultrastructurally. (2) Spherical deposits of amorphous material scattered throughout the cerebral cortex and easily seen with periodic acid-Schiff (PAS); the core of the aggregates is the protein amyloid, surrounded by degenerating nerve terminals (neuritic plaques) that stains with silver. Amyloid is also scattered throughout the cerebral cortex in a nascent “diffuse” form, without organization or core formation and then is appreciated mainly by immunohistochemical methods, as well as deposition in the walls of small blood vessels near the plaques, so-called congophilic angiopathy. (3) Granulovacuolar degeneration of neurons, most evident in the pyramidal layer of the hippocampus. This last change is least important in diagnosis but there is uncertainty regarding its nature; it had been thought to be simply a reactive process but recent studies suggest it reflects a defect in phagocytosis of degraded proteins.
Neuritic plaques and neurofibrillary changes are found in all the association areas of the cerebral cortex, but it is the neurofibrillary tangles and quantitative neuronal loss, not the amyloid plaques, that correlate best with the severity of the dementia (Arriagada et al). If any part of the brain is disproportionately affected with these changes, it is the hippocampus, particularly the CA1 and CA2 zones (of Lorente de Nó) and the entorhinal cortex, subiculum, and amygdala. These parts have abundant connections with other parts of the temporal lobe cortex and dentate gyrus of the hippocampus and undoubtedly account for the amnesic component of the dementia. The associative regions of the parietal lobes are another favored site. Only a few tangles and plaques are found in the hypothalamus, thalamus, periaqueductal region, pontine tegmentum, and granule-cell layer of the cerebellum.