ALZHEIMER'S DISEASE

degenerative brain disorder that develops in mid- to late adult life and results in a progressive and irreversible decline in memory and various other cognitive functions. The disease is marked by the destruction of nerve cells and neural connections in the cerebral cortex of the brain and by a significant loss of brain mass. Alzheimer's disease is the most common form of dementia (q.v.). The disease develops differently among individuals, and this suggests that more than one pathologic process may lead to the same outcome. Typically, the first symptom to appear is forgetfulness, as short-term memory and immediate recall become impaired. As the disease progresses, memory loss becomes more severe and the person's language, perceptual, and motor skills deteriorate. Mood becomes unstable, and the person tends to become irritable and more sensitive to stress and may become intermittently angry, anxious, or depressed. In advanced stages, the individual becomes unresponsive and loses mobility and control of body functions; death ensues after a disease course lasting from 2 to 20 years but typically taking 5 to 10 years. About 10 percent of those who develop the disease are younger than 60 years of age. These cases, referred to as early-onset familial Alzheimer's disease, result from an inherited genetic mutation. The majority of cases of Alzheimer's disease, however, develop after age 60 (late onset); they usually occur sporadicallyi.e., in individuals with no family history of the diseasealthough a genetic factor has been identified that is thought to predispose these individuals to the disorder. The disease was originally described in 1906 by Alois Alzheimer, a German neuropathologist. In the autopsy of a 55-year-old person who died with severe dementia, he noted the presence in the brain of two abnormalitiesneuritic plaques and neurofibrillary tangles. It was principally the identification of neurofibrillary tangles, which had not been described before, that defined the new disease entity. Because Alzheimer's disease was first noted in a relatively young person, it was long regarded as a form of presenile dementia (dementia not associated with advanced age). However, the same brain lesions have been recognized in the brains of many individuals of advanced age who suffer from dementia, and the term Alzheimer's disease is now applied to persons of any age. Neuritic plaques and neurofibrillary tangles are still the primary features used to diagnose Alzheimer's disease in autopsy. Both structures, which also may be found in smaller amounts in the brains of healthy elderly persons, are thought to interfere in some way with normal cellular functioning. However, it is not known whether the plaques and tangles are a cause or a consequence of the disease. Neuritic plaques, also called senile, dendritic, or amyloid plaques, consist of deteriorating neuronal material surrounding deposits of a sticky protein called amyloid b-protein. This protein is derived from a larger molecule, amyloid precursor protein, which is a normal component of nerve cells. Neurofibrillary tangles are twisted protein fibres located within nerve cells. These fibres consist of a protein, called tau, which normally occurs in neurons. When incorrectly processed, tau molecules clump together, forming tangles. Other features have been noted in the brains of many persons with Alzheimer's disease. One characteristic is a deficiency in the level of the neurotransmitter acetylcholine. This observation is significant because neurons containing acetylcholine play an important role in memory. Abnormal concentrations of aluminum also have been found to accumulate in neurofibrillary tangles and neuritic plaques, but it is not known whether the element plays a causative role in the disease. Underlying genetic defects have been identified for the early-onset familial cases of Alzheimer's disease. The first genetic mutation to be discoveredin 1991was localized to a gene on chromosome 21 that codes for amyloid precursor protein. Defects in this gene are thought to increase the production or deposition of amyloid b-protein, which forms the core of neuritic plaques. This gene, however, is responsible for only 2 to 3 percent of all early-onset familial cases of the disease; the remainder are attributed to two other genes: one on chromosome 14 that accounts for 70 to 80 percent of these cases, and one on chromosome 1 that is responsible for about 20 percent of cases. Another gene, on chromosome 19, is thought to play a part in the majority of Alzheimer's cases, the late-onset form. This gene directs production of apolipoprotein E, which is involved in cholesterol transport. There are three forms of this geneApoE2, ApoE3, and ApoE4one of which, ApoE4, is associated with a higher risk of disease. No cure has been found for Alzheimer's disease. The drug tacrine slightly slows the progression of the disease, but it is not effective in all patients and it can become toxic to the liver. Most treatment aims to control the depression, behavioral problems, and sleeplessness that often accompany the disease.