Growing public awareness and the number and quality of Association grant applications reflect the increasing importance of Alzheimer's disease and the growing stature of Alzheimer research. The sense of urgency arising from the impending public health crisis has attracted some of the best minds in science to the effort to unravel Alzheimer's mysteries.
Expanding interest in dementia has nurtured a worldwide initiative exploring a wide array of disease mechanisms and approaches to treatment. Following is a summary of current developments in Alzheimer's research, written for nonspecialists.
Most scientists agree that the critical biological events leading to the behavioral and clinical problems of Alzheimer's center around loss of communication among certain nerve cells and eventual destruction of these cells. Divergent perspectives on the exact cause of this destruction have fostered different theories about what initiates the process and how best to intervene.
Amyloid hypothesis
The theory with the largest following remains the "amyloid hypothesis," which assigns a central role to abnormal processing of amyloid precursor protein (APP), a protein found widely throughout the body but whose normal function remains unknown.
This abnormal processing yields a fragment called beta-amyloid (A?), which aggregates by stages into the amyloid plaques that are one hallmark Alzheimer pathology. Proponents of the amyloid hypothesis see production and aggregation of A? as the key event in nerve cell disruption and destruction.
About half of the applicants to the Alzheimer's Association grants program propose investigations into various aspects of amyloid.
Insights into the steps involved in amyloid processing have already led to identification of two potential therapeutic approaches. One tactic relies on various strategies for stimulating an immune system response that destroys A?.
The first immunotherapeutic compound to reach clinical trials-the "Alzheimer vaccine"-failed to fulfill its early promise. Even though that trial failed, the effort may still yield valuable insights into amyloid and its role as well as point the way to refinements of the immunotherapeutic approach that may yet bear fruit.
The second amyloid-targeting strategy inhibits enzymes called secretases that cut APP into successively smaller pieces, ultimately producing A?. Secretases are classified as proteases, the same category of enzymes targeted by the protease inhibitors that have revolutionized AIDS therapy. A number of pharmaceutical companies are developing secretases, and the first such drug has reached clinical trials.
Nerve growth factors
Another promising drug that reached human clinical testing stimulated production of nerve growth factors, proteins that regulate nerve cell maturation, survival, and repair. Nerve growth factors are an active area of research in stroke, spinal cord injury, and other nerve-damaging conditions as well as in Alzheimer's disease.
Memantine, an Alzheimer drug already approved in Germany that recently won preliminary approval in the rest of the European Union, is now under development in the United States where it has reached Phase III trials. Because memantine treats Alzheimer symptoms in a different way than the four currently approved drugs, some of the Phase III trials are exploring whether individuals may be able to take both types of drugs simultaneously.
Tau theory
The second most prominent Alzheimer theory assigns a causative role to tau, a protein that normally helps organize and stabilize a cell's internal "skeleton." In Alzheimer's, tau deforms and loses its ability to support the cell, eventually aggregating into neurofibrillary tangles-the other hallmark Alzheimer brain lesion.
Although no therapies targeting tau have reached clinical trials, many experts remain convinced that understanding tau will reveal crucial clues about Alzheimer's devastating effects on nerve cells as well as chemical steps vulnerable to intervention.
Inflammation and Alzheimer's pathology
Other projects focus on inflammation as a key part of Alzheimer pathology. Epidemiological studies have revealed that individuals taking anti-inflammatory drugs to treat such conditions as arthritis appear to have a lower-than-expected occurrence of Alzheimer's.
Scientists have launched several clinical trials to investigate specifically whether use of anti-inflammatory drugs may reduce Alzheimer risk. Meanwhile, basic research proceeds to investigate the molecular mechanisms that may underlie the protective effects of anti-inflammatories.
Expanding interest in dementia has nurtured a worldwide initiative exploring a wide array of disease mechanisms and approaches to treatment. Following is a summary of current developments in Alzheimer's research, written for nonspecialists.
Most scientists agree that the critical biological events leading to the behavioral and clinical problems of Alzheimer's center around loss of communication among certain nerve cells and eventual destruction of these cells. Divergent perspectives on the exact cause of this destruction have fostered different theories about what initiates the process and how best to intervene.
Amyloid hypothesis
The theory with the largest following remains the "amyloid hypothesis," which assigns a central role to abnormal processing of amyloid precursor protein (APP), a protein found widely throughout the body but whose normal function remains unknown.
This abnormal processing yields a fragment called beta-amyloid (A?), which aggregates by stages into the amyloid plaques that are one hallmark Alzheimer pathology. Proponents of the amyloid hypothesis see production and aggregation of A? as the key event in nerve cell disruption and destruction.
About half of the applicants to the Alzheimer's Association grants program propose investigations into various aspects of amyloid.
Insights into the steps involved in amyloid processing have already led to identification of two potential therapeutic approaches. One tactic relies on various strategies for stimulating an immune system response that destroys A?.
The first immunotherapeutic compound to reach clinical trials-the "Alzheimer vaccine"-failed to fulfill its early promise. Even though that trial failed, the effort may still yield valuable insights into amyloid and its role as well as point the way to refinements of the immunotherapeutic approach that may yet bear fruit.
The second amyloid-targeting strategy inhibits enzymes called secretases that cut APP into successively smaller pieces, ultimately producing A?. Secretases are classified as proteases, the same category of enzymes targeted by the protease inhibitors that have revolutionized AIDS therapy. A number of pharmaceutical companies are developing secretases, and the first such drug has reached clinical trials.
Nerve growth factors
Another promising drug that reached human clinical testing stimulated production of nerve growth factors, proteins that regulate nerve cell maturation, survival, and repair. Nerve growth factors are an active area of research in stroke, spinal cord injury, and other nerve-damaging conditions as well as in Alzheimer's disease.
Memantine, an Alzheimer drug already approved in Germany that recently won preliminary approval in the rest of the European Union, is now under development in the United States where it has reached Phase III trials. Because memantine treats Alzheimer symptoms in a different way than the four currently approved drugs, some of the Phase III trials are exploring whether individuals may be able to take both types of drugs simultaneously.
Tau theory
The second most prominent Alzheimer theory assigns a causative role to tau, a protein that normally helps organize and stabilize a cell's internal "skeleton." In Alzheimer's, tau deforms and loses its ability to support the cell, eventually aggregating into neurofibrillary tangles-the other hallmark Alzheimer brain lesion.
Although no therapies targeting tau have reached clinical trials, many experts remain convinced that understanding tau will reveal crucial clues about Alzheimer's devastating effects on nerve cells as well as chemical steps vulnerable to intervention.
Inflammation and Alzheimer's pathology
Other projects focus on inflammation as a key part of Alzheimer pathology. Epidemiological studies have revealed that individuals taking anti-inflammatory drugs to treat such conditions as arthritis appear to have a lower-than-expected occurrence of Alzheimer's.
Scientists have launched several clinical trials to investigate specifically whether use of anti-inflammatory drugs may reduce Alzheimer risk. Meanwhile, basic research proceeds to investigate the molecular mechanisms that may underlie the protective effects of anti-inflammatories.
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