Neuroscience Meeting To Feature Feisty Debate On Alzheimer's Etiology

Alzheimer's Etiology Author: Robert Finn SIDEBAR: Sources of Information on Alzheimer's Research The annual meeting of the Society for Neuroscience has long featured "special interest socials"-low-key, early-evening events typically providing members of particular subfields with an opportunity to listen to brief presentations and network with their colleagues over sips of wine and nibbles of cheese. But at this year's meeting (to be held November 11-16 in San Diego), one of the 24 get-togethers promises to be just a bit more exciting. It will air opinions on the most polarizing controversy in Alzheimer's disease (AD) research in a public argument among four high-profile AD researchers. CHAIRWOMAN: Alison Goate, herself a key amyloidologist, will lead next month's debate. This clash of the titans will be a semi-formal debate over the motion "This house believes b-amyloid deposition causes Alzheimer's disease," and it will take place on Tuesday, November 14, from 5:30 to 7:30 p.m. Steven G. Younkin, a professor of pathology and pharmacology and director of research at the Mayo Clinic in Jacksonville, Fla., and Dale B. Schenk, director of neurobiology at Athena Neurosciences Inc. in South San Francisco, Calif., will argue for the motion. Robert D. Terry, an emeritus professor of neurosciences and pathology at the University of California, San Diego, and Allen D. Roses, a professor of neurology and neurobiology at Duke University, will debate against the motion. The prominent scientists were brought together by Alison Goate, an associate professor of genetics and psychiatry at Washington University in St. Louis, herself a major player in the controversy. Goate will chair the debate. "This one issue, more than many others, has divided the Alzheimer's research field in the last decade," says Goate. "It's an important issue, which we're certainly not going to resolve as the result of a debate. But I felt it was a good forum for lively discussion in the area, given there is all this new data coming out." Goate was the source of one of the most important pieces of new data with her 1991 discovery that a rare inherited form of early-onset AD was caused by a mutation to the gene encoding amyloid precursor protein (APP), located on chromosome 21 (A. Goate et al., Nature, 349:704-6, 1991). Back in 1907, Alois Alzheimer himself noticed two types of debris-now called amyloid plaques and neurofibrillary tangles -- in the brain tissue of a 51-year-old woman who had suffered from dementia. Ever since then, researchers have wondered whether AD was caused by the plaques, the tangles, or something else. At first Goate's discovery seemed to settle the issue. Plaques are made of b-amyloid. A defect in the APP gene leading to increased amyloid deposition was responsible for the early- onset AD in the family Goate studied. Moreover, a majority of people with Down syndrome, which is caused by an extra piece of chromosome 21, show the brain changes associated with AD after age 40. And other research groups have followed with news that additional mutations that affect amyloid concentration also cause familial forms of AD. But then research out of Allen Roses's group at Duke, published in 1993, seemed to throw a monkey wrench into the neat amyloid hypothesis. Roses's group showed that the pattern of inheritance of the three forms of a lipoprotein called apolipoprotein E (apoE) greatly affects the risk of developing "sporadic" AD, the most common type of the disease (W.J. Strittmatter et al., Proceedings of the National Academy of Sciences, 90:1977-81, 1993; comments on this paper by A.M. Saunders and W.J. Strittmatter, Hot Papers, The Scientist, Jan. 23, 1995, page 16). FOR THE OPPOSITION: Allen D. Roses's 1993 apoE paper sparked controversy. Specifically, apoE comes in three alleles, apoE2, apoE3, and apoE4. Everyone inherits one of these alleles from each parent. E2 is the rarest allele, and people who are homozygous for E2 (E2/E2) often develop a high-cholesterol disease. Those who are E2/E3 have as little as one-fourth the risk of developing AD as those who are E3/E3. But the E4 allele is the one that confers the greatest risk for developing AD. Those who are E4/E4 are 60 times more likely to develop the disease as those who are E2/E3, and even a single E4 allele significantly increases AD risk. Moreover, those with the E4/E4 genotype develop AD at an average age of 68, while the average age of AD onset for those who are E2/E3 is 90. Although Roses's colleague Warren Strittmatter first came upon apoE's role in AD because it binds tightly to b- amyloid, Roses rejects the amyloid hypothesis and favors one involving neurofibrillary tangles as the cause of AD. Neurofibrillary tangles are made of a protein called tau, and tau's role seems to be to stabilize the structure of the neuron's microtubules, much as wooden railroad ties stabilize the alignment of the metal tracks. ApoE2 and apoE3 both bind to tau, preventing it (according to Roses's hypothesis) from becoming hyperphosphorylated. The E4 form, on the other hand, does not bind to tau, and the resulting hyperphosphorylated tau molecules cannot stick to microtubules. Instead, they aggregate into neurofibrillary tangles, which go on to choke the neuron. TRoses's data on apoE's contributions to AD risk have been repeatedly confirmed by other laboratories, and even supporters of the amyloid hypothesis acknowledge the importance of apoE. Dale Schenk, for example, concedes, "ApoE has a profound effect on the risk of Alzheimer's disease -- very solid data there. The argument is that it's an even bigger factor than APP mutations. In terms of sheer numbers of patients that are affected by it, that's absolutely true." Dale Schenk But Schenk and others in the AD research community remain highly skeptical about the rest of Roses's hypothesis. "As a trained biochemist," comments Schenk, "I've seen nothing yet with regard to apoE that suggests to me that there's a bona fide interaction with anything that's relevant to Alzheimer's disease. I'm sure there is, but it hasn't been identified to date." Schenk points out that much of the work on the interaction of apoE alleles with the phosphorylation of tau has been done in vitro at very high, distinctly nonphysiological, concentrations. In any case, the wording of the debate's motion focuses the argument on the still-dominant amyloid hypothesis, not apoE. According to Schenk, the best arguments in favor of the amyloid hypothesis are, first, "in Alzheimer's disease brain tissue there's always Ab [b-amyloid] deposition. The second piece of the argument is the multiple -- and I mean multiple -- mutations throughout the APP molecule that invariably give rise to Alzheimer's disease." Third, adds Younkin, "if you take one of these mutations, as Athena has done in a mouse, and increase expression of one of these mutated forms of the amyloid protein precursor, you will get pathology. They get senile plaques that are very similar if not absolutely identical to the plaques that one sees in the Alzheimer's disease brain." Even proponents of the amyloid hypothesis acknowledge that it suffers from at least one critical flaw: The amount of amyloid in the brain does not correlate with the severity of the disease. And amyloid critics discount the importance of the AD-causing APP mutations, pointing out that they account for only a tiny percentage of AD cases. As for the third argument, Terry, for one, is eager to discuss the relevance of Athena's mouse model. "I look forward to that argument," he declares, "because I think we can debate it clearly as to whether those plaques mimic the human to some extent only, and not entirely. And what behavioral changes [are there]? And are they the only changes? Is the amyloid the critical change? I know it isn't." Terry, who has been studying AD since 1960 and who is considered by many to be the dean of American neuropathologists, maintains, "Amyloid is a red herring. They've shown us all kinds of data about this protein -- almost as much as any other protein I can think of. . . . And they have not shown it specifically relevant to the pathogenesis of the disease." "Let me give you the thing I tell eighth-graders," says Roses. In lectures to lay audiences he'll display a slide depicting a cemetery with rows of tombstones. These tombstones, he notes, definitively mark the locations of bodies buried below. However, he continues, "Nobody makes the assumption that the people who have been buried there have been killed by their gravestones. [Plaques] are absolute markers required for the diagnosis of Alzheimer's disease. But that doesn't mean that that's what causes Alzheimer's disease." "The idea that amyloid deposition is a kind of a tombstone at the end of the process is just ludicrous," Younkin counters. "It could be that amyloid deposition is something that occurs at the end of the disease. [But] if that were true, then you would not see all the genetic mutations initiating changes that cause amyloid deposition." And Younkin doesn't believe that the lack of correlation between amyloid deposition and AD severity is a problem. He uses the analogy of atherosclerosis. One person's circulatory system could have a great many of the artery- blocking plaques that are the hallmarks of the disease without their leading to a life-threatening blood clot. Someone with many fewer plaques, could suffer a heart attack if they close off a critical artery. One thing is clear -- the argument over amyloid has an angry edge that belies the notion that scientists are dispassionate seekers of truth. "I think that the discussions in Alzheimer's disease are more polarized than would be ideal," says Younkin. "I think that that is a consequence of two things: the personalities of some of the individuals involved and the very high stakes. There's a lot of money to be made if one can find a drug for Alzheimer's disease." "For anybody who is working on some other aspect of Alzheimer's pathogenesis, it's difficult to get funding because of the dominance of the one hypothesis," contends Terry. "I think that's bad science, bad sociology." And of the amyloidologists, Roses adds, "They've held the field. They've ruled the granting process. They've ruled the publishing. It becomes very difficult when the people who review and the people who edit and the people who decide what's being published, 80 percent of them have a viewpoint that stems from amyloid." Alison Goate agrees that the argument over amyloid causes feelings to run quite high: "I think that in a climate where getting research dollars is getting more and more difficult, this polarization has led to there being reviewers for or against the view of whether b-amyloid is involved or not. I think it's had an effect on people's funding." When asked about the charge that amyloidologists make it harder for alternative hypotheses to get funded or published, Younkin replies, "not if I'm reviewing. No way." He adds: "Personally, I think that's terrible if it's true. In fact, I've seen some of the people who are real good working on tangles sort of edge over toward amyloid. And I've watched that happen with real regret. We need people working on those other things." Neither of the two main organizations advocating support for AD research takes a position on the amyloid hypothesis. Daniel P. Perry, executive director of the Washington, D.C.- based Alliance for Aging Research, says, "We've worked on the 'rising tide raises all boats' principle, and don't try to pick winners or losers between different theories." And Sheryl Williams, vice president of medical and scientific affairs for the Chicago-based Alzheimer's Association, says, "We don't actually have any place in this particular debate." The National Institutes of Health is the largest supporter of research on Alzheimer's disease, primarily through the National Institute on Aging. NIH support for Alzheimer's disease research in fiscal year 1995 was $311 million. The Alzheimer's Association is the largest private source of support for AD research. It provided funding of $5.5 million during its most recent annual grant cycle. Although the combatants in this contest are quite passionate about their beliefs, in the end they all strike more or less conciliatory notes. Schenk, for example, comments: "What I would like to see is [that] we come away not excluding one or another viewpoint, but actually incorporating them all together. It's such a devastating disease. If there's more than one way to tackle it, that would be great." o Robert Finn, a freelance science writer based in Long Beach, Calif., is online at finn@earthlink.net. (The Scientist, Vol:9, #20, pg.14 , October 16, 1995) (Copyright © The Scientist, Inc.)

Neuroscience Meeting To Feature Feisty Debate On Alzheimer's Etiology

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