When German physician Alois Alzheimer first identified the disease that bears his name, he had observed severe memory loss and confusion in a woman far too young for the dementia associated with advanced age. After she died, these unusual symptoms led Alzheimer to examine her brain at autopsy; only then did he discover distinctive, diagnostic markers—microscopic clumps of sticky plaque and tangled nerve fibers.

 

Fast-forward a century, and a race is on to invert that sequence and enable diagnosis of Alzheimer’s long before the onset of symptoms. An even more heated contest is under way to introduce drugs that can delay the loss of independence, quality of life, and even identity that Alzheimer’s entails. At the heart of both challenges is something called “the amyloid hypothesis.”

 

This hypothesis rests on the idea that in people with Alzheimer’s disease, a protein fragment normally found throughout the body somehow goes awry. Amyloid-beta, also known as “A-beta,” normally circulates between cells. But in 1984, scientists Dr. George Glenner and Caine Wong isolated A-beta within some of the types of distinctive brain damage Alzheimer noted under his microscope. In the mid-1990s, other Alzheimer’s disease researchers pushed that discovery further. Working independently, Dr. Steven Younkin and Dr. Dennis Selkoe used genetic information derived from a small subset of Alzheimer’s disease patients to sharpen the focus on a specific type of A-beta composed of 42 amino acids—just two longer than the typical A-beta fragment. According to the amyloid hypothesis, rogue A-beta builds up in the brain and disrupts the normal functions of brain cells, leading to inflammation, plaques, and brain cell death.

 

The drugs furthest along in the race to develop a treatment for Alzheimer’s target A-beta or A-beta 42 in some way. Flurizan, steered by Utah-based Myriad Pharmaceuticals, seeks to lower A-beta 42 production by inducing the body to produce shorter strings of A-beta. The drug is well into Phase III trials involving about 1,600 patients.

 

Nipping at its heels is bapineuzumab, a monoclonal antibody driven by Ireland-based Elan Pharmaceuticals and New Jersey-based Wyeth. Bapineuzumab, which aims to bind A-beta and clear it from the brain, is currently in Phase II studies involving about 200 patients, and Elan-Wyeth plans to launch a Phase III trial before the end of the year. 

 

If these drugs succeed in demonstrating a safe, disease-modifying effect, their impact on the market will be enormous. Nitasha Manchanda, an analyst with Massachusetts-based healthcare research firm Decision Resources, estimates that sales of Alzheimer’s-related drugs would leap from about $1.7 billion in 2006 to more than $5.6 billion in the United States in 10 years. That estimate, however, came before the recent failure of one key drug in a clinical trial. Nevertheless, she estimates that bapineuzumab, currently considered the more effective and costly, could bring in about $3.6 billion alone.

 

The reason for such a sizable market is obvious. According to the Chicago-based Alzheimer’s Association, more than 5 million Americans now have the condition, By 2050, the group estimates, with population growth and increasing life expectancy putting more people at risk, that figure could reach 16 million.

 

Alzheimer’s attacks the more complex aspects of brain function first, often destroying memory or the ability to think through a problem logically. Eventually, typically over the course of about eight years, cumulative brain damage proves fatal. According to a U.S. Senate report, public spending on Alzheimer’s may top $110 billion a year in direct and indirect care costs, but even funding on that scale does not cover all of the estimated $170,000 in additional lifetime care costs an Alzheimer’s patient faces.

 

 And medicine today can offer little help. The handful of Alzheimer’s-related drugs currently on the market, such as Pfizer’s Aricept or Forest Laboratories’ Namenda , only ease a few symptoms, most notably memory loss. Since they don’t address the underlying disease process, the drugs only aid some patients for a few years at most.

 

“Eventually, people decline to the same point they would have anyway,” says Dr. Adam Boxer, an Alzheimer’s specialist who directs studies of new therapeutic agents at the University of California, San Francisco. “The drugs just delay the effect. They’re just helping the brain to function a bit better while these devastating changes are going on.”

 

“It’s a boon and a curse, this unmet need,” Manchanda says. “It really moves things along, but it also means things move along with a lot of questions.” 

 

Some question “the amyloid hypothesis” itself. Skeptics dispute whether A-beta really causes the disease, and ask if amyloid plaques in the brain could simply be a symptom of the illness rather than a trigger. While critics present a wide variety of alternative theories, they all say that accumulation of A-beta in the brain can’t fully explain the complex nature of the damage produced by Alzheimer’s disease. Ongoing drug trials are as much a test of the amyloid hypothesis as the new therapies themselves.

 

“A-beta is a part of normal life,” says Dr. Dale Bredesen, CEO of the Buck Institute on Age Research, based in Novato, California. At his independent research center, Alzheimer’s scientists take a contrary view of A-beta, studying whether its effects on cell signaling, not just its mere presence in the brain, cause illness. “The current dogma that this is a toxic disease leaves a lot to be explained. It doesn’t explain why you make normal A-beta all the time.”

 

And Alzheimer’s is proving to be no exception to the usual perils of drug development. Earlier this year, Alzhemed, a once-promising drug from Quebec-based Neurochem, failed its Phase III trial in North America. The company, while stating that the trial results showed no statistically significant effect in treating Alzheimer’s, said it will continue to evaluate options for the medication. Investors, however, drove the company’s stock price deep into the single digits this fall.

 

Elan-Wyeth’s bapineuzumab faces its own challenges, especially a history of safety concerns. Elan and Wyeth’s joint work on Alzheimer’s immunotherapy started more than five years ago. In human trials that attempted to stimulate the patients’ own bodies to bind and remove A-beta, some participants showed signs of benefit, but about 6 percent of the trial subjects developed severe brain inflammation, bringing the research to a halt.

 

Bapineuzumab tries to build on the success of that earlier effort while avoiding its safety problems. The drug, a specifically targeted, laboratory-produced antibody, still aims to bind and remove A-beta from the brain. But while the earlier attempt tried to stimulate patients’ own immune systems to do that work, bapineuzumab is a “passive immunotherapy” agent that targets A-beta without stimulating a patient’s own immune response. Backers say this passive approach makes the drug and its effects much easier to control, reducing the risk of brain inflammation.

 

But other safety concerns remain, such as the possibility that the compound could trigger small bursts of bleeding in the brain. The Phase II trial design, for example, precludes participants with a history of stroke.

 

No data has yet been released from bapineuzumab’s ongoing Phase II trial. But scientists at Wyeth, who have more than 20 Alzheimer’s-related research projects underway, say their work so far indicates an improved safety profile.

 

With a passive approach, “you can determine how much antibody you give someone,” says Dr. Menelas Pangalos, Wyeth’s vice president for neuroscience research. “If there’s an adverse event, you withdraw the antibody and it disappears. It’s a much better

controlled reagent.”

 

According to study data presented by Myriad and a researcher involved in the drug’s initial development, early trials of Flurizan raised few safety concerns. Current Phase III trials in the United States and Europe are expected to wrap up in the first half of 2008, with data to follow later in the year. Analysts project the drug could hit the market in late 2009 or 2010. So far, its benefits center on slowing the decline of early-stage Alzheimer’s patients, allowing them to retain function and continue to live at home for a longer period. A follow-up study of Phase II trial participants also found that longer use of the drug brought mild improvement in memory. To Alzheimer’s patients, any relief from a bleak future looks great.

 

“I’m very anxious to see how it works, once we’re sure I’m getting the real thing,” says Joseph Weibel, 73, a retired publishing executive from Vero Beach, Florida, who has mild Alzheimer’s disease and joined Flurizan’s Phase III trial in early 2006.

 

Weibel doesn’t know if the pills he has been taking twice a day for 18 months are the real drug or a placebo. But he knows he’ll be getting Flurizan starting this fall, as part of the trial’s follow-up. “Then I’ll be able to tell if there is significant recall. The worst thing I have is remembering.’’ 

 

“I don’t know if there is going to be any amazing silver bullet,” says UCSF’s Boxer, who works with the university’s Center on Memory and Aging. “But hopefully there will be diagnostics, along with treatments of mild efficacy, that we can combine to treat people in substantial ways. It’s exciting to think we’re going to get a handle on this disease in the not-to-distant future.”

 

So far, no drug appears to substantially repair Alzheimer’s-related brain damage or dramatically reverse the course of the disease. If an Alzheimer’s patient already has serious brain injury, there might be little point in using the medications.

 

“Is it a good thing to slow the course of the disease if your brain is pretty much toast?” says Dr. Todd Golde, a Mayo Clinic scientist based in Florida who was one of the first to realize Flurizan might help in Alzheimer’s. “But for patients with mild disease, we have to get this right. This is a huge problem, and there are no effective therapies right now. ”

 

Before people develop full-blown Alzheimer’s disease, they usually experience a condition called mild cognitive impairment, or MCI. The signs of MCI, such as minor memory loss, can be so subtle that many people miss them, or dismiss them as routine “senior moments” that come with aging. Alzheimer’s researchers say that A-beta deposits and damage are already well underway in these peoples’ brains. If more of them could be caught early, and the new drugs work at limiting brain destruction, doctors could start therapy before serious illness sets in.

 

Most current methods for diagnosing Alzheimer’s and MCI rely on cognitive tests that assess skills such as memory or problem solving. But scientists are aiming for more precise—and much earlier—detection. Some of the most promising techniques for early diagnosis rely on positron emission tomography (PET). By combining this basic technique with amyloid imaging agents such as Pittsburg Compound B (PiB) or FDDNP, researchers have been able to detect Alzheimer’s markers in those with only mild cognitive impairment. In the United States, the work has received a significant boost from the Alzheimer’s Disease Neuroimaging Initiative, a public-private partnership driven by the federal National Institute on Aging. The six-year program, launched in 2004, brings about $60 million to the study of imaging and other biomarkers, such as A-beta levels in blood or cerebrospinal fluid, in diagnosing Alzheimer’s disease.

 

“I don’t think we’re going to use the word ‘cure,’ says Dr. Susan Molchan, until recently ADNI’s program director. “But we hope to slow the progression of Alzheimer’s. The hope is the earlier you get that, the more you can maintain people at a higher level of function longer.”

 

UCSF’s Boxer, for example, focuses his research on brain imaging that would detect the buildup of A-beta long before a person falters on a cognitive test. At the Mayo Clinic’s division in Jacksonville, Florida, leading A-beta researcher Younkin is working on blood or spinal fluid tests that would track a person’s levels of different A-beta fragments, looking for telltale ratios linked to increased Alzheimer’s risk. He hopes, in the future, that A-beta testing becomes as routine as a cholesterol screen.

 

“You would draw plasma, or tap their cerebrospinal fluid, and see what’s happening with their A-beta ratios,” Younkin says. “If you see a certain ratio, that’s a pretty good predictor. Then maybe you want to do a brain scan. You confirm there is amyloid in the brain. At that point, you initiate therapy.”

 

Analysts say Alzheimer’s imaging technologies could launch commercially by 2011, shortly after at least one of the drugs now in Phase III trials is expected on the market.

 

The amyloid hypothesis has a significant head start in driving Alzheimer’s research and drug development, but different approaches to A-beta, genetic factors, tangles of nerve fibers, and a nerve-cell building block called tau are also worthy of investigation. 

 

At the Buck Institute for Age Research, scientists have created a strain of mice with brains packed with A-beta plaques. But the rodents show no sign of memory loss. Buck scientists say that is because the signaling process between brain cells is still intact, despite the presence of plaques. According to Bredesen, the research demonstrates that Alzheimer’s is more a disease of brain signaling than A-beta toxicity. Beyond better understanding the intricacies of A-beta, however, he hopes the scientific community will uncover much broader findings about this increasingly prevalent illness.

 

“Why is Alzheimer’s so common? Are we going to find viruses associated with this? Will it have a big dietary component?” Bredesen asks. “I think the next five or 10 years will be extremely interesting, and not just because we have ways to slightly reduce A-beta.”

 

Within the next decade or two, says Wyeth’s Pangalos, “We’ll know whether the amyloid hypothesis is right. If it is, we’ll have disease-modifying drugs. If not, we’ll still be trying to treat symptoms.”

 

The Mayo Clinic’s Younkin calls Alzheimer’s “the most major devastating disease of aging.” “The reason it’s so frightening is that it attacks what is uniquely you,” says William Thies, vice president of medical and scientific relations for the Alzheimer’s Association. “You can have four or five heart attacks and you walk down the street and you still look like you. As you begin to attack someone’s personality, you attack who they really are.”

 

As insurance against those bleaker prospects, Alzheimer’s disease scientists and advocates are pushing hard to boost federal funding for Alzheimer’s research, which rang in at a relatively paltry $645 million in 2007. A bill now before the U.S. Senate would pump up that amount over the next five years, hitting $1.3 billion by 2012. This money, advocates say, is essential to basic research that won’t translate easily into big drug profits. And if the new drugs can hold the line against Alzheimer’s, the Alzheimer’s Association’s Thies also sees a need for new rehabilitative medicine, similar to the therapies stroke patients receive to restore speech or movement.

 

“The next few years are going to be very important,” Thies says. “We will look at them as having been a bit of a turning point. We are in the early stages of an epidemic, and we have to do something now.”