Although Alzheimer’s disease was first defined in 1906, the first explanation of a possible cause of the disease was not presented until the 1990’s, when Dennis Selkoe and others described molecular changes in proteins found in the brain tissue of Alzheimer’s disease patients.
Recognition of senile dementias dates back as early as the eighteenth century, though the terms represented a legal state as well as a clinical one. Knowledge of pathological changes, including those represented by plaques and “neurofibrillar bundles” in the brains of some of these patients, dated to at least the late nineteenth century.
In 1901, a fifty-one-year-old patient was admitted to the state asylum in Frankfurt, Germany, with mental confusion, loss of memory and other symptoms of a neurological disorder. Alois Alzheimer, a physician at the hospital, was among the first to observe the patient. In 1903, Alzheimer moved to the Anatomical Laboratory at the Royal Psychiatric Clinic at the University of Munich. The patient died in 1906, and her brain was sent to the clinic, now headed by Alzheimer. Using a new silver staining procedure, Alzheimer observed the unusual fibril tangles in the diseased brain. While acknowledging that his observations were not the first, Alzheimer presented his work at the November 3 meeting of psychiatrists in Tübingen in 1906 and published his presentation the following year. In 1910, Emil Kraepelin coined the name Alzheimer’s disease (AD) to denote the specific type of dementia described by its namesake. In 1911, Alzheimer described a second type of pathological change in nerve cells of the cerebral cortex, calling them Pick bodies, for Czechoslovakian neurologist Arnold Pick, an earlier observer of the deposits.
The plaques and neurofibrillary tangles (NFTs) or bundles described by Alzheimer have become the basis for the specific designation of a senile dementia as Alzheimer’s disease. Found in the regions of the brain that control “higher brain functions,” the plaques are located outside the affected nerve cells and are composed of aggregated pieces of a small protein called beta-amyloid (Β-A). Tangles located within the nerve cells are composed of a protein called tau. Current research strongly supports the hypothesis that formation of the neurofibrils is the basis for development and progression of Alzheimer’s disease.
Alzheimer’s disease causes the volume of the brain to shrink substantially.
Beta-amyloid was first isolated in 1984 by University of California, San Diego, researchers George Glenner
Evidence for the association of Β-APP and AD was initially indirect. Certain types of AD have a clear genetic basis, developing in relatively young persons and tending to run in families. Mutations were found in these patients in which defects occurred in the gene that encodes the Β-APP, resulting in formation of plaques. The gene was located on chromosome 21. Persons with Down syndrome, a genetic defect characterized by mental retardation, have an extra copy of chromosome 21 and also exhibit the deposits typical of AD at an early age. Finally, in the 1990’s it was observed that high concentrations of the processed form of Β-APP, Β-A, form fibrils identical to those in brain tissue of AD patients.
The ability to study Β-APP outside of the body resulted in the discovery of other types of mutations that lead to AD. Furthermore, mutations in the gene that encodes Β-APP were found to account for only a small proportion of familial cases of AD. Understanding the process by which the precursor is converted to Β-A led to the discovery of certain proteases that carry out the actual cleavage. Chromosomal studies involving the families in which AD was commonly found led to identification of a region on chromosome 14 that appeared to carry the mutation. In 1995, two closely related genes designated presenilin 1 and presenilin 2 were identified by Peter St. George-Hyslop and his coworkers as encoding the enzymes that carry out the process. In 1999, Selkoe reported that specific mutations in either of the two presenilin genes cause an increase in the quantity of the Β-A protein, leading to the development of AD. Clearly, improper processing of the precursor form of the amyloid protein plays a critical role in development of AD, and perhaps in other forms of dementias likewise characterized by similar types of fibrils. In recent years, a fourth type of mutation, encoding apolipoprotein E (ApoE), has been studied for its possible role in AD. ApoE is thought to be involved in the assembly of the fibrils.
The discoveries by Selkoe and others have led to formation of a working hypothesis explaining development of AD. The precursor of the Β-APP is inserted in the cell membrane, likely performing a signaling function. Improper processing of the protein, whether due to changes in its amino acid sequence or mutations in the cleaving enzymes, the products of the presenilin genes, somehow results in the tangled fibrils of Β-A. In turn, the fibrils interact with the neuronal membrane, causing changes in the internal tau proteins and ultimately the death of the cell. The progressive nature of the damage leads to development of AD.
At the beginning of the twenty-first century, it was estimated that some 4.5 million Americans were suffering from Alzheimer’s disease, a number that had doubled over the preceding twenty-five years. It has been estimated that more than 4.5 million persons worldwide develop the disease each year, and it has been projected that by the year 2050, some 16 million Americans will have developed AD. The National Institute on Aging has estimated that the annual cost of caring for AD patients in the United States is in excess of $100 billion; this figure will rise as the number of patients increases. Such cost estimates do not address the nonmonetary costs of the disease, such as the stress on patients’ families.
Research into AD since the end of the twentieth century has involved three primary areas: the cause of AD, better methods of diagnosis, and possible treatments to delay the onset, if not find a cure. The work carried out by Selkoe and his colleagues provided one of the first insights into the molecular mechanisms by which the pathological processes develop in the brain. Evidence has been accumulating that the initial steps that lead to degeneration of neurons may actually begin years, even decades, prior to the onset of symptoms. The identification of specific defects associated with AD may not only explain how the disease develops but also provide an early test to identify persons at increased risk. The very fact that AD is progressive may also suggest a point of attack; interruption in the process of neurodegeneration has the potential to prevent, or at least delay, the onset of symptoms. The discovery that the absence of certain genes linked to AD, such as the ApoE gene, may actually protect the individual lends further credence to the role played by these sites in the affected individual.
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Black, Ira. The Changing Brain: Alzheimer’s Disease and Advances in Neuroscience. New York: Oxford University Press, 2002. Fictionalized description of the development of AD in a patient and its impact on his life and family. Also included is the history of neuroscience as it applies to the function of the brain. -
Smith, Patricia, et al. Alzheimer’s for Dummies. Hoboken, N.J.: John Wiley & Sons, 2003. One of the books in the popular series covering numerous topics. Addresses most major questions associated with AD, including symptoms, likely progression, and treatment, in a clear and concise manner. -
Tanzi, Rudolph, and Ann Parson. Decoding Darkness. New York: Perseus Books, 2001. Description of the research into causes of the disease and factors that may contribute or delay its progress, as well as discussion of the impact of AD on families. -
Taylor, Richard. Alzheimer’s from the Inside Out. Baltimore: Health Professions Press, 2006. The author, diagnosed with AD, provides personal input into progression of the disease, personality changes, and increasing difficulty in communicating with colleagues and loved ones. -
Wolfe, Michael. “Shutting Down Alzheimer’s.” Scientific American 294 (May, 2006): 72-79. Summary of the latest research into the cause of Alzheimer’s disease, as well as prospects for detection and treatment.
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