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Alzheimer's disease: Mind mysteries

Experts hope that genetics will pry open the black box regarding the pathology of this disease

By Mark Moran, amednews correspondent. April 2, 2001.

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Mapping Disease
As the results of the Human Genome Project began to shake out into clinical applications, this 2001-02 series detailed progress in the prevention and treatment of a variety of diseases and conditions -- both on the near horizon and possibilities far into the future.

In the early 1980s, pioneers in the nascent field of genomics, among them Rudi Tanzi, PhD, were racing to make a map of the entire chromosome 21. The shortest of the human chromosomes, 21 was known to be anomalous in a number of ways -- not the least of which was that individuals born with an extra copy of it were fated to have Down syndrome.

At about the same time, researchers studying the pathology of Down made an intriguing discovery: The brains of individuals with the condition who had reached a certain age invariably revealed accumulations of an insoluble protein of unknown origin or function, known as amyloid. The potentially sinister role of amyloid plaques in cognitive dysfunction was underscored by the fact that the same substance was found in the brains of patients with another disease -- an insidious malady that robbed them of memory, reasoning and even the remnants of self.

"It turns out that by the time patients with Down syndrome reach middle age, they invariably have the same pathology as patients with Alzheimer's disease," said Dr. Tanzi, professor of neurology at Harvard Medical School and director of the genetics and aging unit at Massachusetts General Hospital.

The terrible serendipity of amyloid in these two disorders would prompt Dr. Tanzi, competitors and colleagues to seek a cause for Alzheimer's on the same chromosome 21 -- giving birth to a genetic approach to a disorder still only dimly understood, even on a biological level. By the end of the decade, linkage between a cohort of Alzheimer's patients with early-onset disease was made to a gene resting on 21, known as the amyloid precursor protein gene, named for the protein it encodes. A mutation in the APP gene, it appeared, would cause abnormal amounts of A-beta-42, a smaller protein cleaved from the amyloid precursor protein, to accumulate in the brain, causing amyloid plaques. [...]