Scheibel and coworkers have described a loss of neuronal dendrites in the aging brain, particularly the horizontal dendrites of the third and fifth layers of the neocortex. However, the Golgi method, which was used in these studies, is difficult to interpret because of artifacts. The morphometric studies of Buell and Coleman showed that the surviving neurons actually exhibit expanded dendritic trees, suggesting that even aging neurons have the capacity to react to cell loss by developing new synapses. With advancing age, there is an increasing tendency for neuritic (amyloid and neurofibrillary) plaques to appear in the brains of nondemented individuals. At first the plaques appear in the hippocampus and parahippocampus, but later they become more widespread. These are loose aggregates of amorphous argentophilic material containing amyloid. They occur in increasing numbers with advancing age; by the end of the ninth decade of life, few brains are without them. However, as shown by
Tomlinson and colleagues (1968  and 1970), relatively fewer plaques are present in the brains of mentally intact old people, in contrast to the large numbers in those with Alzheimer disease (Roth et al). Even more impressive is the correlation of neurofibrillary tangles and Alzheimer disease. Very few such tangles are found in the brains of mentally sound individuals, and those that are found are essentially confined to the hippocampus and adjacent entorhinal cortex. By contrast, neurofibrillary tangles are far more abundant and diffusely distributed in patients with Alzheimer disease.
The view is often expressed that neuritic plaques and Alzheimer type of neurofibrillary changes simply represent an acceleration of the natural aging process in the brain. Most investigators are more inclined to the idea that they represent an acquired age-linked disease, analogous in this respect to certain cerebrovascular diseases or osteoarthritis. In support of this latter view are several observations. First, Homo sapiens is the only animal species in which Alzheimer neurofibrillary changes and neuritic plaques are regularly found in the aging brain. A few plaque-like structures (but no neurofibrillary changes) have been seen occasionally in old dogs and monkeys but not in mice or rats. It seems unbiologic that human aging should differ from that of all other animal species. Second, some of the most severe forms of Alzheimer disease occur in middle adult life, long before old age. Third, these histopathologic changes in variable proportion occur in a number of other diseases unrelated to aging, such as dementia pugilistica (“punch-drunk” state), Down syndrome, postencephalitic Parkinson disease, and progressive supranuclear palsy. Fourth, neurofibrillary tangles can be reproduced in the experimental animal by such toxins as aluminum, vincristine, vinblastine, and colchicine. Finally, a small proportion of Alzheimer cases are definitely familial, as described in Chap. 38.
Virtually every molecular structure within the cell is subject to age-related biochemical modifications, such as the formation of carbonyl proteins, glycation of sugars, and oxidative changes in lipids. Some of these subcellular phenomena contribute to the aging process (see Mrak et al for details), as do the accumulation of mitochondrial DNA mutations and shortened lengths of the telomeres. Among the visible biochemical alterations is an increasing accumulation of lipofuscin granules in the cytoplasm of neurons, sometimes extreme in degree. Also, there is an age-related neuronal accumulation of iron and other pigment bodies. Granulovacuolar changes are a regular finding in aging hippocampi, regardless of the mental state of the individual. The accumulation of glycogen-containing concretions (corpora amylacea) around nerve roots and diffusely in the subpial space is yet another aging effect, which has no known clinical correlate.