State of Alzheimer's Research

The long race to develop a cure, or even a viable treatment, for Alzheimer's disease is quickly turning into a sprint as the Baby Boomer generation heads toward old age and the country faces what could be a health care disaster if the disease is allowed to run rampant.

Scientists nationwide are edging in on possible causes of Alzheimer's, a devastating neurological disease that attacks short-term memory first and destroys brain cells until sufferers can no longer recognize loved ones or take care of themselves, and eventually die from complications such as pneumonia.

But even as an avalanche of research and exciting new areas for investigation developed in the past five years, there have been clinical failures and frustrating setbacks. No one yet knows what, exactly, causes Alzheimer's, and there are only four drugs on the market now to treat it -- none of them very effectively.

Still, there are positive signs. At least two major pharmaceutical companies are in the final stages of clinical studies for drugs that focus on the protein that most scientists think is the likely cause for the disease. A South San Francisco lab is also redesigning a vaccine that failed in a clinical trial four years ago, but some scientists still believe it could stop Alzheimer's.

"The major question still remains: What causes Alzheimer's disease? To know that will take us a very long time, but you can treat a disease without knowing exactly what causes it," said Tony Wyss-Coray, an associate professor of neurology at Stanford University School of Medicine.

"With the population aging, Alzheimer's is going to ruin the health care system. But I think there is really hope that something will work in the next two to five years. It will not completely prevent the disease or reverse it, but it will have an effect on the disease process."

Scientists will meet at Stanford today for an annual Alzheimer's Association conference to discuss the latest research and treatments, from imaging techniques to detect the disease at its earliest stages to upcoming clinical trials and techniques for caring for sick individuals.

About 4.5 million Americans have Alzheimer's now, although that number could be far larger if it included the millions of people who are in the early stages of the disease and have yet not had it diagnosed. And the oldest Baby Boomers, now in their 60s, are heading into the decades when Alzheimer's is most likely to strike.

About 5 percent of people ages 65 to 74 have Alzheimer's disease, and by age 85, people have a nearly 50-50 chance of suffering Alzheimer's, the National Institute on Aging says. The number of new cases is growing every year, and by 2050, the affliction could strike 14 million Americans.

Alzheimer's is a particularly upsetting disease, and nearly every American is familiar with its debilitating effects, either first-hand from taking care of a parent or grandparent, or from watching the disease take down public figures such as President Ronald Reagan and actor Charlton Heston.

"It scares the bejesus out of people," said William Fisher, chief executive of the Alzheimer's Association for Northern California. "If what's between your ears is compromised, that's a fundamental difference. It's not like losing your backhand or your knees giving out. It's a hard thing for people to talk about. They don't even want to think about it."

Alzheimer's was discovered a hundred years ago by a German doctor who studied a rare type of Alzheimer's that hits people in their 30s and 40s. The more common disease that affects the elderly has been around probably for hundreds of years, or even thousands of years, but it is mostly a result of decades of health-care progress that allows people to live much longer.

It was only about 35 years ago that serious research into Alzheimer's started, and it wasn't until the 1990s that scientists started developing real theories on where to focus treatments. The first drug to treat Alzheimer's was approved by the FDA in 1993.

"I think with Alzheimer's, we're now at where we were with cancer in the '70s," said Charles DeCarli, an associate professor of neurology at UC Davis Medical School and director of the university's Alzheimer's Disease Center. "We have a sense of the problem, we know where we'd like to be in 20 years, but we don't know how we're going to get there. We're not having a big impact."

That has to change, and fast, DeCarli said. "Alzheimer's kills you. Your five- or seven-year mortality is about 50 percent," he said. "If you're 60 years old, that's a big deal. We're not playing around here."

Indeed, Alzheimer's research has accelerated in the past five years, and new studies are released just about every week. The National Institutes of Health report 95 studies worldwide related to Alzheimer's are either actively recruiting participants or are expected to begin recruiting soon.

"What we're seeing now is an explosion in understanding Alzheimer's that is underpinned by the last 30 years or so of very, very fundamental, basic science," said Marcelle Morrison-Bogorad, director of the National Institute on Aging's Neuroscience and Neuropsychology of Aging Program. "Now we have second- and third-generation research."

Alzheimer's research received about $650 million this year in federal funding -- more than double the funding 10 years ago, although this year was the first in a decade that funding didn't increase.

Nearly every major pharmaceutical company in the world has some sort of drug therapy in the works. The disease is potentially big business for the pharmaceutical industry, and everyone is racing to come up with the first major advance in treatment, said Howard Fillit, executive director of the Institute for the Study of Aging in New York who also serves on an advisory board for Neurochem, a Montreal pharmaceutical company that is in the final testing stages of a drug to treat Alzheimer's.

"Five years ago," he said, major pharmaceutical companies "did-n't think enough was known about Alzheimer's, and it was too risky to develop drugs. They were wary of getting into it."

But a lot of the major companies "see that clearly there's a market out there now," he said. "They are getting involved, and the venture capitalists are looking for good opportunities.

"Alzheimer's is the most important disease of the 21st century. Clearly, we need to be making a lot more investment in drug discovery research both in academia and in industry."

Recent research has been aided by the "brain decade," when scientists in the 1990s made major progress into understanding the brain and the billions of chemical processes that take place in our minds.

Scientists also created a new kind of transgenic mouse model that allowed them to genetically modify lab mice so they would carry a type of Alzheimer's that is pathologically similar to the disease humans have, opening up new areas of research.

No one yet knows what exactly causes Alzheimer's disease, but scientists agree that one of the most likely causes is a protein called amyloid that, when broken into smaller pieces, builds up in the brain and leaves messy piles of plaque that pollute the space between neurons, or brain cells. For years, the prevailing theory was that this plaque disrupted communication between neurons and ultimately killed brain cells.

But recent research suggests that it isn't the plaque that interrupts communication between neurons, but individual amyloid protein molecules that float between cells. The plaque buildup, argue some scientists, may be a mostly harmless side effect of Alzheimer's, not the cause. The individual protein pieces "hit nerve cells like cruise missiles," attacking the energy centers of the neurons, said Lennart Mucke, director of UCSF's Gladstone Institute of Neurological Disease.

Whether it's the plaque or the protein missiles that cause Alzheimer's, there is little doubt among scientists that amyloid is an important research target -- how to destroy it, stop it from interfering with neuron functions, or prevent it from building up in the brain in the first place.

Other research areas also look promising. Scientists are studying another protein, apolipoprotein E4, which carries with it a higher risk of developing Alzheimer's. "ApoE" proteins maintain and repair neurons.

There are three common types of inherited apoE -- E2, E3, and E4 -- and E4 is the only one that seems to lead to Alzheimer's. Scientists at Gladstone are looking at a treatment that would alter the E4 so it behaves more like the E3 protein and doesn't attack brain cells.

A third focus for research is inflammation in the brain, which can cause blood vessels to constrict and limit the amount of blood carried to the brain. Depending on the type of inflammation, it can either start chain reaction that leads to amyloid-beta buildup, or in some cases prevent that buildup.

The ultimate therapy for Alzheimer's probably will involve a cocktail of drugs -- much the way doctors treat cancer and AIDS -- that attack the disease from several different points, scientists said.

"The diversified portfolio idea is very sensible," Mucke said. "We often end up treating patients with different drugs. I think we will end up treating Alzheimer's in a similar fashion."

Both Neurochem in Montreal and Myriad, a pharmaceutical company based in Salt Lake City, are in final, stage-three trials toward developing drugs that would be the first to attack the protein at the center of Alzheimer's disease, instead of just treating the symptoms.

A therapy developed by the South San Francisco lab of Elan Pharmaceuticals that would vaccinate people against amyloid buildup has been redesigned and is once again in clinical trials. In 2003, Elan was forced to halt its study of an Alzheimer's vaccine after the tests caused serious brain inflammation in 15 patients.

After mouse therapy looked so promising, Gladstone's Mucke said, Alzheimer's research has been plagued by disappointing study results and human trials that fail. It's a notoriously difficult field of study, he said, because so little of the brain is understood, and because the population most afflicted often suffers from other age-related diseases that confuse research data.

"In general it's not easy to come up with effective treatments for any disease," Mucke said. "The problem with Alzheimer's is it affects an age group when other diseases exist and muddle up the picture.

"The last 20 years have resulted in a much greater understanding of the causes of the disease. It's just not been easy to develop drugs that are effective and safe. There are very promising therapeutic entry points. We have to push to the finish line."

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Alzheimer's disease: destroyer of thoughts and memories

More than 50,000 Americans die of Alzheimer's disease annually. This neurological disease takes away a person's ability to remember, speak, move and control his or her life. Research into the mechanism of the disease is continuing, and one key theory is it involves the interruption of the neuronal networks by sticky clusters of protein fragments called amyloid beta peptides. Researchers are expecting the total number of U.S. cases to rise from 4.5 million today to more than 14 million by 2050.

Amyloid beta: Brain cells secrete a protein called amyloid. When this protein is broken into pieces, a section known as amyloid beta is created. Amyloid beta is thought to be at the center of what causes Alzheimer's disease.

Amyloid plaque: Lumps of amyloid beta that build up around neurons in the brain were once thought to be the cause of Alzheimer's. Many scientists now think the plaque could be a mostly harmless side effect.

Oligomers and protofibrils: When amyloid beta pieces don't form into plaque, they can create much smaller clusters. Many scientists now think these oligomers and protofibrils attack neurons, disrupting communication between cells and eventually killing them.

Neurons: Humans have billions of these nerve cells in the brain.

Synapses: Tiny gaps between neurons. Brain cells communicate by sending chemical messengers, called neurotransmitters, through synapses to cause responses in the brain.

Sources: UCLA School of Medicine, The J. David Gladstone Institutes

John Blanchard / The Chronicle

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