In July the Washington, D.C., Hilton was inundated by some 2,500 Alzheimer’s disease researchers from many different countries. They had come for the World Alzheimer Congress 2000, the largest international Alzheimer’s meeting ever convened. People packed conference rooms, even sat on the floors, but it didn’t seem to matter; they were eager to hear, to ask questions, to share information.

Indeed, there was good reason for their ebullience. There have been remarkable advances in understanding Alzheimer’s during the past decade, and findings continue to pour out of labs at lightning speed. The first drugs ever to be approved for treating Alzheimer’s—the cholinesterase inhibitors—have become available during the past four years. And some new treatments now in the hopper may well turn out to go farther than the cholinesterase inhibitors do in countering the Alzheimer’s disease process.

True, the some 1,000 scientific presentations at the congress had to do with many different subjects. Yet if the presentations could be said to share any one theme, it would have to be a protein called beta amyloid—the stuff from which plaques in the brains of Alzheimer’s patients are made. Many Alzheimer’s researchers believe that it is central to the disease process.

For instance, there are correlations in the human brain between beta amyloid accumulation and cognitive function, and in vitro tests have revealed that beta amyloid is capable of causing nerve degeneration, reported Carl Cotman, Ph.D., of the University of California at Irvine.

Beta amyloid in turn derives from a protein called amyloid precursor protein.

The normal metabolism of this protein is mediated by an enzyme called alpha secretase. Although they have not isolated it yet, they know that it exists from indirect evidence. Or as Steven DeKosky, M.D., of the University of Pittsburgh School of Medicine, explained it, it’s like "coming home and seeing that your lawn is mowed, but not seeing the lawnmower—yet you know there must be one because the grass clippings are there."

The amyloid precursor protein can also be snipped by two other enzymes, which scientists named beta secretase and gamma secretase. Their existence also was first revealed by indirect evidence—that is, if there are clippings, there must be something doing the cutting—DeKosky said. Yet beta secretase has since been isolated, and perhaps gamma as well, he pointed out, and when the amyloid precursor protein is snipped by either beta secretase or gamma secretase, beta amyloid is formed, which results in plaques.

What’s more, mutations in three different genes are capable of causing early-onset Alzheimer’s, and all of these mutations increase the production of beta amyloid, reported Rudolph Tanzi, Ph.D., of the Massachusetts General Hospital and Harvard Medical School. One is a gene for the amyloid precursor protein; the other two are genes that make, respectively, proteins called presenilin 1 and presenilin 2. And as Bruce Yankner, M.D., Ph.D., of Harvard Medical School pointed out, the presenilin proteins have been shown to be associated with the amyloid precursor protein; are involved in beta amyloid production; seem to be required for gamma secretase production; and may even be gamma secretase. In fact, Michael Wolfe, Ph.D., of Brigham and Women’s Hospital and Harvard Medical School, said that he and his colleagues are now trying to determine whether the presenilin proteins and gamma secretase are one and the same.

Amyloid processing is also implicated in late-onset Alzheimer’s, reported Steven Paul, M.D., of the Eli Lilly Company in Indianapolis. Apolipoprotein plays an important role in lipid metabolism. A mutation in the gene that makes apolipoprotein, called E4, is known to lead to plaque formation in the brain, and some 50 percent of people who get late-onset Alzheimer’s have this E4 variant.

What these and related advances have done, then, is to give scientists ideas on how to thwart excessive amyloid production in the brain as well as specific physical targets in the brain to attack. They are hoping that at least one of their strategies will dramatically counter Alzheimer’s—something that drugs currently on the market do not do, although they may be somewhat more effective than many people suspect (see box).

For instance, Dale Schenk, Ph.D., of Elan Pharmaceuticals in San Francisco and his colleagues used a synthetic copy of human beta amyloid to immunize six-week-old mice. The mice had been genetically engineered to express a mutant human amyloid precursor protein gene that causes early Alzheimer’s in humans and that, in mice, leads to the neuropathological hallmarks of Alzheimer’s disease. The immunization essentially prevented the development of plaques in the brains of the animals. The researchers then used the synthetic beta amyloid to immunize the same kind of mice at 11 months of age, when amyloid plaques were already well established in their brains. This treatment markedly reduced the extent and progression of plaques.

"Our results raise the possibility that immunization with beta amyloid may be effective in preventing and treating Alzheimer’s disease," they concluded in the July 8, 1999, Nature.

Since then, Schenk explained at the World Alzheimer Congress 2000, they have tested the beta amyloid vaccine on 24 patients with mild to moderate Alzheimer’s disease, and it appears to be safe. They will now be testing it further for safety in 80 patients. If all goes well with the safety tests, they will conduct clinical trials to see whether it can counter Alzheimer’s in humans. "We are cautiously optimistic," Shenk said.

Meanwhile, results from a Canadian animal behavior study reported at the congress underscore the potential of a beta amyloid vaccine against Alzheimer’s. David Westaway, Ph.D., and colleagues at the University of Toronto used beta amyloid to immunize mice that had been genetically engineered to express a mutant human amyloid precursor protein gene that causes early-onset Alzheimer’s in humans and that, in mice, results in Alzheimer’s-like neuropathology and problems in learning and memory. (The strain was not the same as that used by the Elan researchers, although it results in similar neuropathology.) The mice were given the vaccine at six weeks of age, then again at eight weeks of age. After that they were given a water-maze test to measure their spatial-memory ability, as were identical genetically engineered mice that served as controls. The vaccinated mice performed better on the test than did the control mice, suggesting that the vaccine had improved their spatial memory.

Regardless of whether beta amyloid immunization pans out as an effective Alzheimer’s therapy, altering the expression of the mutant gene that makes apolipoprotein and that plays a role in late-onset Alzheimer’s might be another way of heading off Alzheimer’s, Paul suggested. He and his colleagues at Eli Lilly are trying to find a drug that can counter such expression.

Still another possible therapeutic strategy, Kevin Felsenstein, Ph.D., of Bristol-Myers Squibb, explained, is to find a drug that can inhibit one of the two enzymes known to form beta amyloid—gamma secretase. Felsenstein and his colleagues are working in this direction and so far have found some promising candidates that decrease beta amyloid in the brains of animals after a single dose and within 12 hours of administration.

In a related talk, Perry Molinoff, M.D., of Bristol-Myers Squibb reported that researchers there already have a clinical trial under way with one of these compounds, and so far it seems to be well tolerated in subjects. Whether it can reduce plaque progression and lead to therapeutic benefits remains to be determined.

At a Congressional briefing held in conjunction with the World Alzheimer Congress 2000, Donald Price, M.D., of Johns Hopkins University School of Medicine in Baltimore and one of the congress organizers, pointed out that it is enormously important that researchers in search of an Alzheimer’s cure, such as the Bristol-Myers Squibb team, now have enzymes that they can target. This was not possible until recently, he said. Although Bristol-Myers Squibb investigators seem to be the furthest along in finding an effective drug that can counter these enzymes, other drug companies are working on it as well, he told Psychiatric News, and information about their findings should be emerging during the next few months.

In their race to find a highly effective treatment for Alzheimer’s disease, it seems, researchers cannot make progress fast enough. Four million Americans currently have Alzheimer’s, Leon Thal, M.D., of the University of California at San Diego pointed out at the congressional briefing. Whereas there were only 600,000 new cases of dementia in the United States in 1996, 2.4 million new cases can be expected in 2050. Moreover, Alzheimer’s is increasing in prevalence not just in the United States, but throughout the world. And even if efforts to find a cure simply result in a drug that can delay the progression of the disease one year, that too would have value, he contended, because it would not only spare human suffering but save considerable money. Currently it costs $40,000 a year on average to care for an Alzheimer’s patient.

Indeed, whatever Alzheimer’s scientists can come up with will be appreciated by nearly all Americans because, as Rep. Chris Smith (R-N.J.) pointed out at the congressional briefing, "Every one of us. . .is touched by this terrible disease."