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Closing in on Alzheimer's

With many new drugs on the path to approval, scientists expect to deal a major blow to the disease within 10 years, if not five.

By STEPHEN NOHLGREN
Published February 27, 2007


Hardly a week passes without some drug company or research lab trumpeting new progress against Alzheimer's disease.

Genetic clues, experimental drugs that turn lab mice into furry Einsteins, even caffeine.

It always sounds so promising, so just around the corner.

Yet people with wandering spouses and delusional parents have cause for skepticism. For years, they have pinned hopes on similar pronouncements, with no real relief.

That may change soon.

A century after a German psychiatrist identified Alzheimer's and decades after researchers discovered the first genetic link, scientists are quietly confident that they will slow the disease to a crawl within 10 years, if not five.

Nine new drugs are in Phase III clinical trials, the final stage before the government decides whether a drug is safe and useful. An additional 23 are in Phase II.

These are not today's Band-Aid therapies, which merely juice up the brain. These drugs are designed to attack the disease directly and prevent further damage.

It's the difference between prescribing painkillers for cancer and discovering how to kill it with radiation and chemo.

On a parallel path, other researchers are developing tools to detect Alzheimer's early, maybe even before symptoms appear. That way, people at high risk of dementia can start taking medicine in their 40s and 50s.

"All of these things combine to generate a tremendous sense of hope in the field," says Bill Thies, medical spokesman for the national Alzheimer's Association. "We are on the verge of some really good things."

The financial stakes are enormous.

Medicare and Medicaid spend billions of dollars a year on Alzheimer's patients, who cost three times more than average patients to treat. As baby boomers age, they are expected to triple the caseload if science doesn't come through soon.

"Alzheimer's is an emerging epidemic. We have to look at it with the same urgency that we looked at AIDS and cancer," says Harvard professor Rudolph Tanzi, a research pioneer. "It has the potential to completely break the health budgets of this country."

The phalanx of new drugs coming through the experimental pipeline attacks the disease from several directions.

"With so many people taking shots on goal," Tanzi says, "somebody's going to hit it."

Rare case throws researchers off trail

More than any other major disease, Alzheimer's is a product of aging. Few people get it before 65, but by 85, two out of five people show symptoms.

Research was delayed, however, because Dr. Alois Alzheimer, who first identified the disease, was treating a 51-year-old woman who had a rare case of what we now call early onset Alzheimer's.

An autopsy showed that her brain was clogged with sticky clumps of protein known as plaques, like boulders strewn around a living room.

Nearby neurons, the cells that process memories, had shriveled and died. Proteins inside neurons had balled up into strange tangles.

It was a serious disease all right, but no need to sound the alarm. After all, few 50-year-olds contracted it.

For half a century, nobody connected that woman's autopsy to 80-year-olds who suffered from "senile dementia" or "hardening of the arteries," polite ways of describing loopy behavior.

Society simply accepted those symptoms as normal aging.

Dementia became more prevalent in the 1960s and '70s because more people were living longer. When a few curious researchers autopsied older brains, up popped Dr. Alzheimer's sticky plaques and tangled neurons.

"It was the same process, the same pathology, the same biochemistry," says Thies of the Alzheimer's Association. "It shifted from a disease of minor neurological interest into a huge public health problem."

On the verge of understanding

Alzheimer's plaques are composed mostly of a substance called amyloid, bits of protein that float around the brain and eventually start sticking together.

Researchers aren't sure what role, if any, amyloid plays in a healthy brain. But at some point, it seems to get out of control, triggering inflammation and other harmful reactions that kill brain cells - sort of like a big rock that falls off a cliff and sets off an avalanche.

Seven years ago, an Irish drug manufacturer called Elan electrified the research community by vaccinating baby lab mice that had been bred to develop Alzheimer's symptoms when they grew up.

The vaccine, created from synthetic amyloid, stimulated the mice's immune systems to fight off amyloid production as they aged.

Professors at the University of South Florida injected the vaccine in older mice that had already developed sticky amyloid plaques. The vaccine not only cleared out the plaques, but the mice also solved their mazes more quickly.

But when Elan used the vaccine in humans with mild dementia, disaster struck. About 5 percent suffered serious brain inflammation; Elan halted the injections.

That setback shows how maddening the transition from lab mice to human subjects can be.

"Humans and mice aren't identical," says Huntington Potter, director of the Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute in Tampa.

"It's the problem with all research: It looks good in a test tube, then you try it in animals and 10 percent looks good in the animals. Then you try it with people and only 1 to 5 percent end up being a real pharmaceutical in patients."

Nestled within the ill-fated Elan tests, however, was an intriguing result: A handful of human subjects did develop antibodies against amyloid, even though they received only a partial complement of injections.

Four years after Elan yanked the vaccine, four of these patients still showed no mental decline. Four people is too small a sample to conclude that the vaccine stymied their dementia, but drug manufacturers all over the world are scrambling to produce other vaccines.

USF professor David Morgan ran mouse tests for a California company that developed antibodies that clear amyloid in mice without the brain bleeding associated with other vaccines.

Pfizer paid at least $250-million for rights to those antibodies and is conducting clinical trials on humans, Morgan says.

"This is a really exciting time in this field. We are right on the verge of understanding this thing," Morgan says. "Eli Lilly has antibodies in clinical trials. Merck has antibodies in clinical development. Novartis has a novel-type immunotherapy they are testing. Elan has a modified vaccine in active trials.

"I think we will know in the next 18 to 24 months if immunotherapy is going to be useful in Alzheimer's. And therefore whether any other method of trying to reduce amyloid is likely to be useful."

The Roskamp Institute in Sarasota has identified 300 compounds that can lower amyloid in mice, director Michael Mullan says.

Roskamp takes drugs already known to be safe in humans, then tweaks them in the chemistry lab until they morph into something new that lowers amyloid.

Then comes the hard part.

Will the body's normal blood/brain barrier keep the drug from getting into our brains? Will the drug disappear in hours? Will it be toxic?

Most importantly: Will some big drug company take a chance on it, spending millions of dollars testing it on humans, knowing that most such experiments fail?

"It takes about $600-million or so to develop drugs from scratch and about 10 years' work," Mullan says.

At the Mayo Clinic in Jacksonville, researchers got a break when they joined a cancer trial.

Promising drugs, but no silver bullet

For some time, researchers have wondered whether anti-inflammatory drugs, the kind that treat arthritis, might ward off Alzheimer's. Brain inflammation is a telltale sign of the disease, along with amyloid plaques and tangled proteins inside of neurons.

Though early research indicated that some anti-inflammatories fight Alzheimer's, trials were halted when participants developed ulcers and kidney problems.

Mayo's Todd Golde and Edward Koo, at the University of California-San Diego, kept plugging away with a drug called Flurizan, which was intriguing for two reasons:

Its chemical structure is the exact mirror image of an anti-inflammatory called flurbiprofen. Maybe Flurizan can provide the beneficial punch of an anti-inflammatory without destructive side effects.

Flurizan also distinguishes between types of amyloid. Scientists once viewed all amyloid as bad, but most now believe that a version called beta-amyloid 42 is toxic and a more common version, beta-amyloid 40, is probably beneficial.

It's like good cholesterol and bad cholesterol.

Golde and Koo found that Flurizan could lower "bad" 42 in mice and in human cells grown in lab dishes without harming "good" 40.

Under normal circumstances, it would have taken them $50-million to $100-million to run Flurizan through data verification and clinical trials - well beyond their reach.

By chance, a Salt Lake City drug company, Myriad, was cranking up a trial on Flurizan as a possible cancer treatment. Myriad agreed to join forces and test Flurizan for both cancer and Alzheimer's.

A Phase II trial on 207 people with mild to moderate Alzheimer's produced modest results. Those who received the highest Flurizan dose maintained cognition better than the moderate dose group.

But the cancer trial fizzled.

So now, Myriad is running a large Phase III trial just for Alzheimer's, with results due in the summer of 2008.

If the FDA lets Flurizan go to market, even a moderate boost to cognition will stimulate further research to make Flurizan and similar drugs more potent.

"We are not going to make people rise from the dead and walk on water," says Golde, "but if you can keep people from being institutionalized or from having constant supervision at home, all those things are huge pluses."

Whatever drugs hit the market first will earn tons of money but will later yield to more potent competitors, most researchers believe. Eventually, people will probably take several drugs that attack the disease in different ways.

"This is going to be a long haul to get perfection," says Potter, of the Byrd Institute. "There's not going to be a single magic bullet that is going to solve everything - unless we get incredibly lucky."

Stephen Nohlgren can be reached at 727 893-8442 or nohlgren@sptimes.com.