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Indeed, unless these clinical trials run into unexpected snafus, a long and fierce debate may soon be resolved. As the Alzheimer Association's Thies puts it, "Either the beta-amyloid hypothesis is correct, in which case new therapies should come very quickly, or it isn't, in which case researchers at major laboratories will very quickly switch their efforts to more productive directions."
JOUSTING FOR GENES
For nearly a century, scientists have wondered which of the brain lesions associated with Alzheimer's is more important--the plaques that litter the empty spaces between nerve cells or the stringy tangles that erupt from within. The problem arose the moment a German neuropathologist named Alois Alzheimer stared through a microscope at a slice of brain tissue and beheld these twin markers of the disease he was first to diagnose. The year was 1906. The patient's name was Auguste D. She was 55 when she died, and she had spent the last years of her life as a patient in a mental institution. She was prone, Alzheimer noted, to angry outbursts and fits of paranoia, and would sometimes pat the faces of others, apparently mistaking them for her own.
Alzheimer's discovery generated great interest at the time, but the disease that carried his name soon came to be regarded as a medical oddity. Why? For many years, the diagnosis appeared to apply only to a very small group of patients under the age of 60. That soon changed, thanks in part to the widespread use of vaccines and antibiotics, which extended the life-span (from around 50 years in 1906 to 77 today). By the 1960s, the number of cases of so-called senile dementia had increased to the point that neurologists finally made the connection: in most cases, Alzheimer's disease and senile dementia were one and the same (see box, page 56).
It was then that the question of what caused Alzheimer's disease--the plaques or the tangles--began to loom large. In the mid-1980s, researchers isolated beta amyloid--a generic name for a class of sticky proteins--from the brains of Alzheimer's patients. A short time later, four research teams zeroed in on the gene that encodes the recipe for making the protein. To their great surprise, they discovered that beta amyloid was a fragment of a much larger protein, which came to be known as the amyloid-precursor protein, or APP for short.
Almost overnight, it seemed, scientific interest in the genetics of beta amyloid exploded. Researchers had long been aware that early-onset Alzheimer's, while rare, often ran in families. Could it be, they wondered, that the culprit was a mutant version of the APP gene? In 1991 scientists at London's St. Mary's Hospital Medical School screened the DNA of an Alzheimer's family and found what every geneticist in the field had been furiously looking for. The mutant APP gene sat on chromosome 21, and the single change in its DNA sequence occurred in the vicinity of the beta-amyloid fragment.