Biochemistry of Alzheimer's Dementia

The association of dementia in the elderly with microscopic pathological abnormalities in the cerebral cortex was originally made by Alzheimer (1907). Modern commentators prefer not to distinguish between Alzheimer’s disease and senile dementia so that the term dementia of the Alzheimer type (DAT) is often used. The most characteristic mental impairment (for review see Slaby and Wyatt, 1974) is memory loss progressing to disorientation, speech impairment, and confusion. The condition is often accompanied by depression and later by motor hyperactivity. The deterioration is progressive and, quite apart from the distressing personal aspects of the condition, it has become evident that its incidence and the necessity for nursing care have important economic consequences. The associated neuropathological changes (for review see Perry and Perry, 1982) are cortical atrophy (particularly in the presenile forms) and a high density of neurofibrillary tangles and senile plaques in the cerebral cortex. It is important to recognise that these morphological features are found, but with less frequency, in the brains of elderly nondementing patients. The neurofibrillary tangles are found particularly in the perikaryon of pyramidal cells and are composed of large numbers of tightly packed neurofilaments (10-12 nm in diameter) twisted in pairs (Terry, 1963). It had been known for some time that intracranial injection of aluminium salts produces neurofibrillary degeneration that resembles, but is not identical to, that found in Alzheimer’s disease (Terry and Pena, 1965). The parts of the brain in which neurofibrillary degeneration was most extreme also contained higher than normal concentrations of aluminium (Crapper et al., 1976). The high concentration of aluminium was associated with the chromatin, as the aluminium levels in the isolated nuclei were twice thal of control patients. This was not simply nonspecific binding, because patients who had died as a result of dialysis encephalopathy and who had overall brain aluminium contents some 10-20 times higher than normal did not have any greater amounts of aluminium associated with their DNA than the control patients (Crapper et al., 1980). In addition, Alzheirner-affected chromatin has been shown to be less accessible to micrococcal nuclease (EC 3.1.3 1.1) than normal chromatin (Lewis et al., 1981). The senile plaques (20-200 pm in diameter) are found in the neocortex when silver staining techniques are used. They consist of abnormal neuronal processes often intermingled with astrocytes or microglia. Kidd (1964) and Terry et al. (1964) have identified many of the constituent neuritic processes of the plaques as presynaptic boutons. DAT appears in the general population at a frequency of about 1% at age 70, its incidence increasing at approximately 0.3% per annum over the next decade (Heston et al., 1981). Relatives of those with the illness show a much greater incidence of Alzheimer’s disease than the general population (approximately 10% cumulative risk at age 70), indicating the presence of a genetic component in its occurrence. Relatives also have excesses of Down’s syndrome compared with the general population (Heston et al., 1981). A pair of monozygotic twins both of whom developed Alzheimer’s disease has been reported (Cook et al., 1981).