Epidemiology and Etiology

Alzheimer's disease is ultimately a neuropatho-logical diagnosis. A wide variety of gross morphological and microscopic changes occur in the brain of patients with Alzheimer's disease. Unfortunately, many of these changes are difficult to distinguish from alterations that occur in the brain of normal elderly persons, who also show some atrophy of white matter and, to a lesser extent, gray matter.

Neurochemically, Alzheimer's disease has been associated with a decrease in the activity of the en zyme choline acetyltransferase, which synthesizes acetylcholine (Coyle, Price, and DeLong 1983). Acetylcholine is the neurotransmitter most involved in memory circuits. Levels naturally decrease with age, but in patients with Alzheimer-type dementia, choline acetyltransferase may decline to 20 percent of that in age-matched control subjects. Other neurochemical changes associated with Alzheimer's disease include a decrease in gamma-aminobutyric acid, substance P, and somatostatin-like activity in the brain of patients with Alzheimer-type dementia. The significance of these findings is unclear.

Although it is generally recognized that genetic influences are important in Alzheimer's disease, the exact nature of these genetic influences also remains unclear. There are some families that have a large number of members with the clinical or pathological diagnosis of Alzheimer's disease (Cook et al. 1979). The most important practical point regarding these kindreds is that most of them meet criteria for autosomal dominant inheritance. Penetrance of the gene exceeds 90 percent in most of these families. As a result, the children of an affected person have a 50 percent risk of developing dementia if they survive to the age at which dementia begins in that family. The exact proportion of familial cases is unknown, but they may account for as many as 10 percent of all cases of Alzheimer-type dementia (Kokmen 1984). There is some familial clustering in families without dominant inheritance. It would appear that concordance for dementia is somewhat higher in monozygotic versus dizygotic twins, suggesting genetic factors. On the other hand, concordance is not 100 percent, so environmental factors must have a role. Since age of onset varies within a twin pair, it may be difficult to be certain whether a given pair is truly discordant.

An association has been shown also between Alzheimer's disease and families that produce children with Down syndrome (Heston and Masri 1966). Further support for a link between Down syndrome and Alzheimer's disease is provided by the fact that patients with Down syndrome tend to demonstrate neuropathological findings consistent with Alzheimer-type senile dementia if they live to adult life. Since Down syndrome represents a disorder of chromosome 21, a point of origin for the search for the genetic determinants of Alzheimer's disease is suggested. The amino acid sequence for the amyloid that accumulates in the brains of patients with Alzheimer's disease is called the A4 beta-pleated amyloid. The gene for the precursor has been identified, cloned, and mapped to the proximal long arm of chromosome 21 (St. George-Hyslop et al., 1987). Recent data favor the hypothesis of a genetically induced overproduction of amyloid protein as a factor in the cause of Alzheimer's disease.

When families request genetic counseling, one can only explain what is known about the genetic factors. In a family with a single Alzheimer victim, the lifetime risk for a close relative also to develop dementia is approximately 10 percent. Since most dementia develops over the age of 70, this is a relatively small probability. In families with dementia occurring over several generations, an autosomal dominant inheritance is probable, and the risk for children of an affected parent may approach 50 percent. In these families, optimum health management indicates the suspicion of dementia in every elderly person with altered environmental-social interactional skills, multiple physical complaints in the absence of objective disease, or vague and unclear history. Autopsy can be suggested to confirm diagnosis to trace the pedigree more accurately.

Environmental causes for Alzheimer's disease have also been suggested. Some investigators have linked focal intranuclear accumulation of aluminum to the presence of neurofibrillary degeneration in hippocampal neurons. The relationship of aluminum to Alzheimer-type senile dementia, however, is not well accepted (Markesbery et al. 1981). General decline of immunologic competence with aging suggests an autoimmune mechanism. Although elevated levels of brain antibody have been demonstrated in Alzheimer's disease, antineuronal antibodies have not been demonstrated in the central nervous system (Watts, Kennedy, and Thomas 1981). Serum protein abnormalities have been demonstrated, notably changes in haptoglobin functions. Finally, a viral cause has been proposed but not substantiated (Wisniewski 1978).

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Unraveling Alzheimers Disease

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