As scientists learn more about Alzheimer's, the evidence mounts that its cause is at least partly genetic.
The key finding so far has been a protein called amyloid that is present in the tangled brains of Alzheimer's patients, and some researchers believe that rapidly autopsied brain tissue is critical to this line of research.
Last fall, Dr. Dmitry Goldgaber of the National Institutes of Health first located the amyloid protein gene on a particular human chromosome.
A flurry of follow-up research reports last spring by Goldgaber and independent investigators at Harvard University confirmed this; established a provocative link between this amyloid gene and Down syndrome, a form or mental retardation caused by multiple copies of chromosome 21; and found a genetic defect on chromosome 21 in four families that had Alzheimer's through several generations.
Taken together, they produced widespread speculation that the cause of Alzheimer's is indeed genetic and that the amyloid protein gene may be the cause.
And yet other research is perplexing. In the July 3 issue of the journal Science, Goldgaber was one of seven researchers -- including his boss, Nobel laureate D. Carleton Gajdusek -- to report that the messenger code for making amyloid protein was found in normal brains as well.
The researchers hypothesized that the amyloid gene may still play a role but that in Alzheimer's patients, there may be another gene involved -- a regulating gene.
And last week, scientists trying to pinpoint the amyloid gene as the cause of Alzheimer's reported that they had failed. "We are back to square one," one of the scientists said at a news conference.
"There is no consensus whether it is one gene or a collection of genes," Goldgaber says, but he is certain that Duke University's Rapid Autopsy Program will accelerate the search for the answers.
And Goldgaber stresses: "It's premature to go from this data to make a statement that Alzheimer's is a pure genetic disease. I think, and many others do, too, that there is a certain genetic involvement in the disease, that genetics could be the central element."
Crucial to the genetic inquiry now is the ability through rapid autopsy to recover what program director Dr. Allen Roses describes as "high-fidelity messenger RNA."
In human cells, the life instructions are contained in DNA. But in order to perform their daily functions -- like producing a protein -- cells must convert that message into the very fragile and short-lived RNA. Researchers now know that the RNA breaks apart within an hour after death.
By recovering the RNA immediately upon a patient's death and backtracking to the originating DNA code, Roses says, scientists will be able to tell what's going wrong at the most fundamental level -- in the genes of Alzheimer's victims.
Goldgaber now is collaborating with Roses, using the rapid autopsy program's "library" of DNA, to check for genetic differences between normal and Alzheimer's brains.
With further research, Roses is convinced that a means of early diagnosis of Alzheimer's and possibly treatment for it "is not as far down the road as some people might think."
"I believe the new information about Alzheimer's now is going to be almost multiplying exponentially," he predicts.
Roses has been overwhelmed by dozens of requests for tissue from Alzheimer's researchers around the world. Recently, "the requests have skyrocketed to hundreds, including several corporations interested in obtaining exclusive rights to (products derived from) the tissue," he says.
Roses is considering such an arrangement, perhaps selling the rights to a diagnostic test, if "some company is willing to give a huge amount of money to endow the program research."
Among the other research being done on rapid autopsy brain tissue: One group of researchers is working on "chromosome hopping," a technique to more efficiently "jump" along the chromosome in the search for a genetic link. Others are exploring and measuring the proteins and enzymes in the tissue to see which sections of the brain produce them, and which chromosomes direct their production. This could provide clues to the way the disease affects memory and brain function.
Says Duke neurologist Dr. Mark Albert, who is investigating one of these enzymes -- nerve growth factor -- in Roses' laboratory, "There are a cascade of enzymatic reactions going on in the brain, probably involving multiple genes and enzymatic pathways.
"The difference in the various diseases of the brain may be variations on a theme," he suggests. "Isolating a defective gene will tell us a lot about how the brain works . . . and can lead to information about another disease." And the rapid autopsy project has attracted interest from other medical researchers as well. Specialists studying the lung, heart, liver and pancreas are removing tissue immediately after death in a search for clues about diseases affecting those organs.
"When the word got around," says Roses, "others said they would like to have the tissue, so we're cooperating."