Research on Alzheimer's disease is one of the hottest topics in the biological sciences today. In 1992, for instance, two Alzheimer's papers made it into the list of the top 25 cited papers of the year, as compiled by the Institute for Scientific Information of Philadelphia. And in 1991, one paper occupied the second-most-cited slot for that year.
But despite the excitement among researchers, there remains a number of unanswered questions about the underlying mechanisms of the disease. While the most popular theory--that the key to the disease is beta-amyloid, the peptide fragment that accumulates in patients' brains--continues to gain ground, some worry that devoting all research to the beta-amyloid theory may be dangerous.
"If it doesn't pan out, you take about 100 steps backward," says one knowledgeable research scientist at an East Coast biotech company heavily involved in developing drugs that target beta- amyloid production, speaking on condition of...
The beta-amyloid peptide contains approximately 40 amino acids and is the primary constituent of the distinctive plaques that accumulate in the brains of Alzheimer's patients. It's not clear what the normal function of beta-amyloid is, much less its role in the pathogenesis of the disease. Beta-amyloid is a derivative of a much larger, membrane-bound protein called the amyloid precursor protein (APP), and there have been some tantalizing clues discovered in the course of research as to how the larger protein might be broken up to produce the peptide fragment, but the enzymes involved have not yet been found. Biotech and pharmaceutical company researchers are vigorously working to characterize these enzymes and developing compounds that block their action. They see this approach as the fastest route toward developing drugs that will halt the disease's progress.
Beta-amyloid's role in the pathogenesis of Alzheimer's disease-- whether it's a primary cause of the disease or a secondary symptom--continues to engage scientific debate. But Dennis Selkoe, a noted Harvard University neuroscientist who is one of the chief proponents of the beta-amyloid theory, says its role is becoming more firmly established. "In the last five years there's been a steady drumbeat of support for the notion that beta- amyloid deposition can initiate the disease," he says.
Others are still not convinced. Robert Terry, an Alzheimer's researcher at the University of California, San Diego, says, "Everybody thinks beta-amyloid is the key, and I don't." Terry has correlated the degree of dementia in Alzheimer's patients with the loss of synapses in the brain. The proponents of the beta-amyloid hypothesis say that beta-amyloid causes the loss of synapses, but he says, "I don't see the evidence." He says "amyloidophiles" still have to answer the question why the amount of beta-amyloid deposits in a patient's brain doesn't correlate with the severity of the disease. "After all, it's the dementia we care about--we don't care about plaques and tangles if they aren't doing any harm," he adds. "But if they're right, so much the better. Truth will out--that's the great thing about science."
Harvard Medical School neuroscientist Kenneth Kosik, who does research on Alz-heimer's neurofibrillary tangles, says the amount of research on beta-amyloid is out of proportion to other areas of interest in the field. But that's not because there's too much research on beta-amyloid, he says, just not enough on other aspects. "Beta-amyloid is extremely interesting," he says, and when it comes down to divvying up the limited resources, decisions about what gets priority need to be made. But, he cautions, "we need to keep an open mind about other things that may be happening in Alzheimer's disease."
Those "other things" include investigating the role that the tangles play in the disease, since plaques without tangles don't produce Alzheimer's dementia. The tangles are composed primarily of an abnormally overphosphorylated protein called Tau, whose normal function in the brain is to help sculpt the shape of neuronal processes--axons and dendrites. How it becomes phosphorylated to such an extent and what causes it to form tangles are unclear.
The funding outlook for Alzheimer's research is uncertain, especially with a new administration in the White House, says Zaven Khatchaturian, the National Institute on Aging's associate director for the neuroscience and neuropsychology program. Given the federal budget crisis, he says, "under the most optimistic scenario, the funding will not go down."
Kosik says simply spending the same amount on Alzheimer's research is insufficient. "When you weigh the costs incurred by Alzheimer's patients, and the emotional and financial costs to families," he says, "the amount of research is still very small."
Selkoe says potential funding cuts in the federal budget will have to be made up by private sources, like nonprofit fund- raisers, philanthropists, and pharmaceutical companies. While the media can be an ally in calling attention to the need for more funding, he likens Alzheimer's research today to working in a "goldfish bowl," and adds, "I think the scrutiny of the press is understandably a double-edged sword." Selkoe says the press leaps on every paper with the word "Alzheimer's" in the title. "While it's exciting to follow the pace of research," he says, "the public should understand that none of this translates into a treatment today."
Recent developments tend to shore up the theory that beta-amyloid plays a pivotal role in the disease. The discovery in 1991 of a genetic mutation that ties APP to Alzheimer's disease was the first real indication of a link between beta-amyloid production and the pathology of the disease. Alison Goate and her colleagues, then at St. Mary's College in London, made an exciting discovery--a link between an inherited version of Alzheimer's disease and a genetic defect on chromosome 21. That paper, "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease," which appeared in Nature, was the second-most-cited paper for 1991, and to date has been referred to about 250 times in other publications (A. Goate, et al., 349:704, 1991). The point mutation results in a one-amino-acid substitution in a region of the APP protein just outside what ends up as the beta-amyloid fragment. That discovery was followed by other research reporting similar abnormalities.
Harvard's Selkoe says: "That linkage is so clear, even the naysayers agree that in those cases APP appears to be causal."
More recently, genetic defects on chromosomes 14 and 19 have also been linked to familial Alzheimer's. Goate and Selkoe say if beta-amyloid is central to the disease process, then in all likelihood, the genes on those two chromosomes are involved in the processing, transcription, or regulation of APP. Goate says finding out what the gene on chromosome 14 does will either confirm that hypothesis or prove it's caused by a completely different mechanism.
The next key step is to identify how the genetic mutations on all three chromosomes are related to the pathology of the disease. To this end, Goate, now at Washington University in St. Louis, is trying to incorporate the defective APP gene into the genome of a mouse. If the mouse develops Alzheimer's-like plaques as a result, that would be a clear indication. "Human genetics can only give you a statistic," she says. "You need to demonstrate that the mutation is sufficient to cause the disease."
She's battling difficult odds to create an animal model, however. Two of three recently published papers, purporting to show Alz- heimer's-like pathology in transgenic mice, were withdrawn after the data were questioned (D. O. Wirak, et al., "Deposits of amyloid beta protein in the central nervous system of transgenic mice," Science, 253:323, 1991; and S. Kawabata, et al., Nature, 356:23, 1992). And rodents don't normally produce plaques, aged or not; whereas humans, even in the absence of Alzheimer's disease, accumulate beta-amyloid plaques in old age. That's not necessarily an indication that the animal model won't work, just that if it's a negative result, it can't be interpreted as meaning the defect doesn't cause the disease. In estimating her chances of success, Goate says, "you can pick examples on either side."
Other recent findings that lend credence to the beta-amyloid theory are the papers published last fall in the same issue of Nature, by Selkoe and his collaborators, which show evidence that beta-amyloid can be detected in the spinal fluid of both "normal" individuals and Alz-heimer's patients, and is a normal cell product (C. Haass, et al., "Amyloid beta-peptide is produced by cultured cells during normal metabolism," 359:322, 1992; and P. Seubert, et al., "Isolation and quantitation of soluble Alzheimer's beta-peptide from biological fluids," 359:325). What causes it to form the brain deposits and its role in causing dementia still remain important, but unanswered, questions. But the discovery is important because researchers had previously postulated that some sort of injury or genetic defect was necessary to start the cascade of events which produced the beta- peptide.
More important, says Selkoe, now researchers have a way of identifying drugs that could inhibit beta-amyloid production, by testing them in cultured cells. Before, the only place beta- amyloid was seen was in post-mortem Alzheimer brain deposits. The researchers also found that some animals, like guinea pigs, have measurable amounts of beta-amyloid in their cerebrospinal fluid.
"Now there's a way of getting to proof of concept," Selkoe says. "We have to either put up or shut up. Does decreasing beta- amyloid production in the brain, or in the circulatory system, retard the progression of Alzheimer's disease?"
Of course, he acknowledges, that's a leap of faith. "There's plenty of room for healthy skepticism that inhibiting beta- amyloid production would ever help an Alzheimer patient," he says, "and I can't tell you if it will or will not."
Biotech companies, like Athena Neurosciences Inc., based in San Carlos, Calif., which Selkoe helped found, are targeting the enzymes that may liberate beta-amyloid from APP. Although the specific enzymes have not yet been identified, general protease inhibitors are being tested for their ability to reduce the production of beta-amyloid. Dale Schenk, Athena's director of immunochemistry, says his firm's scientists aren't ignoring other possibilities, and are continuing to develop drugs based on nerve growth factors, which may extend the life of neurons.
But these don't get at the essential mechanism of the disease. That's where APP and the beta-peptide come in. "You have to take risks," he says, "and as long as the beta-peptide is the best approach out there, we'll continue to take it." Indiana University's Merrill Benson, who discovered one of the mutations in the APP gene, says the metabolism of APP is very important in understanding Alzheimer's disease. But the field is getting overcrowded, and he feels there are a lot of extraneous papers published on Alzheimer's. He says the key discoveries thus far are finding the beta-peptide, cloning the gene, finding mutations that predict the disease, and discovering the linkages to chromosomes 14 and 19. The hundreds of other papers out there, evidence of the popularity of Alzheimer's research, he says, "clog up the literature." But, he adds, they may add useful insights. "Only after you get to the top of the hill and look back," he says, "can you tell what steps were important along the way."
As for the future, Selkoe says it may be seven, 10, or even 15 years before we understand fully what causes Alzheimer's disease. But, he adds optimistically, "we don't need to understand the whole picture to treat the disease." He estimates that drug trials of a credible candidate that block the early mechanism of the disease could be as little as three to six years off, and possibly even less.`
Diana Steele is a freelance writer based in Takoma Park, Md.