A team of researchers led by Dennis J. Selkoe, professor of neurology at the Harvard Medical School, has come closer to unraveling the deadly secrets behind Alzheimer's disease (A.D.).

Selkoe and his colleagues published their findings last month in the journal Nature Medicine, confirming that mutations in two genes previously known to be connected with early-onset familial A.D., presenilin one and two, do in fact stimulate production of a protein believed to be an important indicator of Alzheimer's.

Scientists have known previously that mutated forms of these genes were found in A.D. patients, but were unsure how they affected the brain.

"This research establishes the genotype to phenotype relations or, in layman terms, how [the gene] does...its dirty work," Selkoe said.

Selkoe says his research found that the mutations in the genes cause the formation of neuritic plaques in the brain which are characteristic of A.D.

"We believe these plaques of amyloid beta short circuit nerve cells, not allowing them to communicate," says Selkoe, co-director for the Center for Neurologic Diseases at Brigham and Women's Hospital.

He says the protein is a common link among Alzheimer's patients.

"We know that 100 percent of Alzheimer's patients have the abnormal buildup of...the amyloid beta protein," Selkoe says.

Consequences of the Disease

Alzheimer's affects an estimated four million Americans, costing more than one hundred billion dollars a year, making it the third most expensive disease to treat in America, according to the Alzheimer's Association of America (AAA).

The disease affects 10 percent of people over 65 and 50 percent of people over 85. It is the fourth leading cause of death in the United States today, said the AAA.

A.D. attacks and destroys neurons in the brain, causing such symptoms as loss of reasoning and memory, triggering the inability to perform simple tasks such as brushing teeth or fixing meals.

After being diagnosed, an Alzheimer's patient lives an average of eight years until dying.

Selkoe says that although they have identified some of the genes which are responsible for A.D., scientists have yet to determine whether the disease is entirely genetic or caused by an outside factor, such as natural radiation.

Selkoe says the plaque is formed by the Amyloid beta (A. beta) protein in the brain, but its formation may serve solely as an indicator of the onset of the disease.

"It has...been pointed out that the total number of A. beta deposits show only a modest correlation with degree of dementia," Selkoe writes in a recent Science Magazine article. "But this is precisely what one would expect from an initiating factor."

The plaque clusters around degenerating nerve endings during the early stages of the disease. However, numerous other cellular changes must take place to degenerate the nerve endings, thus leading to true dementia, he says.

There are two forms of Amyloid beta protein which are in the brain--one with 40 amino acid molecules per polypeptide chain and the other with 42.

The protein A. beta 42 has been discovered to form a plaque before A beta 40, even though the latter is much more predominant. Because of this, much of scientists' efforts in investigating A.D. have been directed at this early sign of the disease.

The recent accumulation of evidence suggests that of the four genes which scientists have so far identified as being connected with A.D., all four operate to increase levels of A. beta proteins in the brain when defective.

Selkoe writes in the Science article, however, that although A. beta may be a necessary factor for the onset of A.D., it may not be sufficient.

A counterargument to the significance of A. beta in the onset of A.D. is that there are sometimes many deposits of A. beta protein in the brains of unaffected people, Selkoe said.

However, he says that the presence of A. beta is not as important as the concentration of the protein present in the individual. Like cholesterol, A. beta tends to becomes toxic only when found in excessive amounts.

"A. beta...is what I call a Jekyll and Hyde molecule," Selkoe says, comparing the protein to Robert Louis Stevenson's famous tale of a scientist gone bad. "It has a good function--a Jekyll function--and then when it builds up, it has a Mr. Hyde function--it becomes toxic."

Searching for A Cure

At the same time that Selkoe and his colleagues' work adds to the weight of studies indicating that A. beta is an early sign of A.D., scientists have begun the search for a mechanism to prevent the formation of the neuritic plaques in the first place.

In the November 12 issue of the Proceedings of the National Academy of Science, a team of researchers, led by Selkoe, reported success in regulating the concentration of A. beta 40 with certain chemical compounds.

The study had a minimal effect on reducing the level of A. beta 42, however. Substantial effects on the protein were achieved only by greatly increasing the total dosage.

Although the study did not have as much success with regulation of A. beta 42, Selkoe says recently developed drugs lower the levels of A. beta 40 and 42 more equally, as opposed to their predecessors which tended to lower A. beta 40 by more substantial amounts.

Selkoe and his colleagues' research points to A. beta accumulation as the common factor among the four known genetic mutations of A.D. The study comes as the most recent in a long series illuminating the behavior of A. beta in the brain.

In response to reports that the cause of A.D. is still a mystery, Selkoe says knowledge of the disease is not as limited as it has been made out to be.

"We do know the cause of Alzheimer's," he says. "We know four different causes [but] we do not know all the causes."