Alzheimer's Disease
Alzheimer disease is a relentlessly progressive degenerative disorder of the human central nervous system that typically begins in middle to late adult life and is manifested by a series of clinical features, with recent and immediate recall being affected more than remote recall.
Abstract
Alzheimer disease is a relentlessly progressive degenerative disorder of the human central nervous system. The disease typically begins in middle to late adult life and is manifested by a series of clinical features. One feature is an impairment of memory, with recent and immediate recall being affected more than remote recall. Another is the loss of ability to perform previously learned complex tasks (e.g., making change, balancing a checkbook). Equally symptomatic is the loss of ability to reason (e.g., understanding a complex conversation, undertaking intellectual hobbies such as chess and cards). Unfortunately, this disease is incurable at the moment. The treatments that are available can only alleviate some of the symptoms, rather than correct the problem. Alzheimer disease is a highly prevalent disorder, which, in Western industrialized nations, affects at least 1 in 10 individuals over the age of 65 and perhaps as many as 1 in 3 individuals over the age of 85. Over a period of 5 to 15 years the disease becomes progressively worse, rendering patients bedridden. This disease is a lethal disorder, with the majority of patients succumbing to complications of their bedridden state (e.g., pneumonia, pressure sores, bladder infections) after 10 to 15 years. Alzheimer’s is the fourth leading cause of death in industrialized societies. At the tissue level, the disease is characterized by three typical abnormalities. One is a profound loss of nerve cells inside the brain. In normal circumstances, the fissures and clefts would be very small and tight. However, due to loss of brain substance, or shrinkage of the brain caused by the disease, those clefts and fissures become wide and vacuous, resembling valleys and troughs. The second pathological feature of the disease is microscopic. Fibrous proteins accumulate inside of the nerve cell within the cortex of the brain, forming dense mats, called “neurofibrillary tangles.” The neurofibrillary tangles are composed of a phosphorylated form of Tau (a cytoskeletal protein, i.e., a protein that normally forms the structure within a cell). The third feature is currently central to research concerning the disease. It is called the senile or amyloid plaque. This is an aggregation of fibrous proteins in the extracellular space, the area outside of a cell and between other cells. Principal among the fibrous proteins in the amyloid plaques is a small protein composed of approximately 40 to 42 amino acids, known as the amyloid beta peptide (Ab). This peptide is derived from a long precursor gene called the b-amyloid precursor protein (b-APP). The cause of Alzheimer’s disease appears to be very complex. Epidemiological studies have suggested that a positive family history, which implies genetic factors, a history of prior significant head trauma, and a history of reduced early education experience may all be risk factors for this disease. Other, less robust epidemiological associations are thyroid disease and exposure to high concentrations of aluminum in the drinking water. With the exception of the genetic risk factors, it is difficult to be sure whether the other environmental risk factors are true causes of Alzheimer’s. They could be surrogate markers for another linked environmental factor or, simply, factors that might nonspecifically lower the threshold of the development of a chronic, slowly progressive, underlying disease. It is likely that in many cases of genetic risk there may be a combination of both genetic and environmental cofactors. For instance, exposure to an environmental trigger might somehow pull the genetically cocked gun, thereby initiating this deathly process. During the past Decade of the Brain, scientists have used the powerful tools of recombinant DNA technology to identify some of the genetic defects that cause Alzheimer’s disease. These genetic factors have provided a solid basis for improving our understanding of the subsequent biochemical events that are initiated by the genes. Because the disease is similar whether Neurobiology of Disease 7, 546–548 (2000)