When the mind takes leave

Illustration of lost mind

New research aims to slow or even prevent Alzheimer’s  

Emory neurologist James Lah

Emory neurologist James Lah

By Martha Nolan McKenzie

In the century since German physician Alois Alzheimer discovered the disease that bears his name, scientists have untangled many of the mysteries of the brain disorder. They have identified the unique pathology of plaques and tangles within the brain that characterize Alzheimer’s disease. They’ve pinpointed brain chemicals involved in the disease’s progress. What researchers have not been able to uncover, however, is a cure or even a terribly effective treatment.

“The treatments we have now for Alzheimer’s are Band-Aids,” says Emory neurologist James Lah. “They treat symptoms but don’t touch the underlying pathology. At best, they slow the progression of a disease that typically spans a decade by about six months.”

Lah and his colleagues are working to change that. Lah is leading a team of researchers in several late-stage clinical trials testing promising disease-modifying therapies. In other words, instead of treating the symptoms, they attack the underlying disease process. He has no illusions that his current work will yield a cure, but he hopes to find a treatment that can significantly slow the disease’s debilitating progress.

“When you say word ‘Alzheimer’s’ to someone, they have an image of somebody who is tremendously debilitated, unable to recognize family members, paranoid, confused,” says Lah. “But many patients are not like that. In fact, if you met someone who was just having beginning symptoms, you may not be able to tell that they have Alzheimer’s at all. If we can delay the progression of the disease by five to 10 years, they may have some difficulty with their memory, but they can appreciate interactions with their grandchildren, enjoy their vacations and hobbies, and never really reach that devastating late stage of the disease before they die of something else.”

Such a treatment can’t come soon enough. More than 5 million Americans have Alzheimer’s, a degenerative disease marked by memory loss and cognitive impairment that is linked closely with age. The risk of developing the disease doubles every five years after the age of 65, and by age 85, up to 30% to 40% of people will develop Alzheimer’s. With the great wave of baby boomers approaching the Alzheimer’s prone years, experts expect an unprecedented swell in cases in the next few decades.

“It’s really staggering,” says Allan Levey, chairman of the department of neurology and director of Emory’s Alzheimer’s Disease Research Center. “We see a tsunami coming. Worldwide there are 35 million people with dementia, most of whom have Alzheimer’s disease. By 2030 that number will almost double, and by 2050, it’s projected to be 115 million. It will take a devastating economic as well as personal toll.”

Gene therapy

Emory is one of 12 universities participating in a nationwide study testing the effectiveness of an experimental medication, CERE-110. In Phase 2, it is the first gene therapy clinical trial for Alzheimer’s.

The CERE-110 trial seeks to prevent or slow the death of brain cells in Alzheimer’s patients by delivering a protein called nerve growth factor (NGF) directly to the affected area of the brain. Lah, who is the principal investigator of the trial, hopes NGF will act like its somewhat notorious kin, erythropoetin, or EPO. A trophic factor that boosts the growth of red blood cells, EPO has been the publicized culprit in cyclist doping scandals.

While EPO promotes the growth and health of red blood cells, boosting an athlete’s performance, NGF nourishes a specific population of brain cells that deteriorate in Alzheimer’s. These cells produce acetylcholine, which plays a vital role in memory and cognitive function. If NGF can keep these cells alive and healthy, then levels of acetylcholine won’t drop as dramatically, leaving memory and cognition intact.

“We’re very early in the trial,” says Lah, “but decades worth of data from rodent models and non-human primates suggest that this therapy can be effective.”

In the trial, a neurosurgeon will inject CERE-110 directly into the area of the brain where neuron death occurs, the nucleus basalis of Meynert. The CERE-110 will deliver the gene for the protein NGF packaged inside an adeno-associated virus (AAV).

“These adeno-associated virus vectors are very safe,” says Lah. “They are very small and can’t reproduce themselves. They can be manufactured in advantageous ways so you can deliver a lot of what you want to deliver in a very small volume.”

After the AAV delivers the gene to the cells, researchers believe the cells then will begin to make NGF from that DNA. Once it does, the cells should continue to churn out NGF indefinitely.

“Once the gene is turned on, it should keep making NGF for the rest of the patient’s life,” says Lah. “We don’t know that for sure, but animal models have shown that production continues for years.”

While current therapies try to stop the chemical breakdown of acetylcholine, CERE-110 holds out the promise of keeping the cells that make the chemical healthy. “This is one of the most exciting first steps to rescue brain cells that we know are important in memory and thinking and that deteriorate in Alzheimer’s disease,” says Levey. “This trial is also important from the perspective of potential of surgical approaches to brain diseases. If a surgery works, it’s a one-time intervention, rather than having to take a pill every day. The CERE-110 trial is a different way to think about how to deliver therapies to the brain and could lead to other therapeutic approaches down the road.”

A vaccine for Alzheimer’s?

Researchers have long been interested in developing a vaccine to immunize people against Alzheimer’s, and indeed, animal vaccine trials in the 1990s were so encouraging that a human trial was launched in 2001.

The vaccine targeted a naturally occurring brain protein called beta-amyloid. Usually harmless, this protein accumulates to excess in the brains of Alzheimer’s patients and sticks together to form one of the distinguishing features of the disease, plaques. These plaques build up between nerve cells, blocking communication between them and eventually causing cell death.

In animal trials, the anti-amyloid vaccine proved highly effective in two ways. In animals that already had signs of the disease in their brain, the vaccine slowed down and in some cases even reversed the pathology. In animals whose brains did not have any signs of disease, the vaccine prevented or drastically retarded disease onset.

Similar results were expected in the human trial, although researchers knew there was a risk that using a live vaccine could provoke an autoimmune response. That is, in fact, what happened. In about 6% of the patients in the study, the immune system not only attacked the beta-amyloid in brain cells but also those in the blood vessels. This caused encephalitis, a life-threatening swelling of the brain, and the study had to be stopped.

So Lah and his colleagues are putting a different spin on the earlier human trials by using preformed antibodies, much like those used to treat people bitten by a rabid animal. “It’s called passive immunity because you’re not triggering the immune reaction in your own body,” says Lah, who is co-principal investigator of the trial. “Instead you are delivering antibodies that are made elsewhere and using that as a tool to clear out something you don’t want to be there.”

Even though no live vaccine is being used, the study participants are being closely monitored with brain imaging. The downside to this treatment, if it proves effective, is that patients would need to get regular infusions of the antibody throughout their lifetime. Lah is not particularly worried about that eventuality, however. “If I had Alzheimer’s, I’d do it!” he says.

Early detection

As promising as the CERE-110 and vaccine therapies are, they still suffer from a major drawback that affects all Alzheimer’s treatments. “The big problem with all therapies is that they’re getting to the party too late,” says Lah.

Though Alzheimer’s is thought of as a disease that typically spans a decade, its actual course is closer to 30 years. By the time the first mild symptoms of memory loss appear, the disease already has been wreaking havoc in the brain for about 20 years. If physicians could catch the disease earlier, treatments would stand a better chance of being successful.

“It’s just like with cancer,” says Lah. “If we identify cancerous lesions early—say, if we catch a small lump in the breast—we can cure you. But if we wait and let it spread, that breast cancer is probably going to kill you.”

Accordingly, Lah and his colleagues are trying to identify brain imaging methods that may show the presence of the disease before symptoms appear. They are actively developing biomarkers that could alert physicians to the presence of Alzheimer’s, much like the prostate specific antigen can signal prostate cancer.

In addition, Lah has developed an inexpensive, brief screening test for mild cognitive impairment (MCI), which is often the earliest stage of Alzheimer’s. Traditional Alzheimer’s screening tests are impractically lengthy at 40 to 60 minutes of formal cognitive testing, which is far beyond the average of 15 minutes that a physician spends with a patient. While these tests are very good at detecting dementia, they pick up MCI only about half the time.

The test Lah and his team developed combines a three-minute cognitive screening test, dubbed the Mini-Cog, and a brief functional activities questionnaire that is filled out by a spouse or someone close to the patient. The results were impressive. Lah says that the test picked up MCI about 80% to 85% of the time, and it picked up MCI plus undiagnosed dementia closer to 95% of the time. Researchers are in the process of validating the results now. If it holds up, this would be a very inexpensive, quick tool physicians could use to screen for early stages of memory loss.

“To tackle the epidemic that is coming down the road, early detection is absolutely critical,” says Levey. “Physicians don’t have the time or the expertise that is needed to really screen their patients. A simple, quick screen would be a big advantage and could identify Alzheimer’s earlier when treatments are more likely to be effective. Lah’s work in this area has been tremendously important.”

Lah is optimistic about the future. “If things go reasonably well, about 20 years from now we should be able to identify the disease earlier and apply treatments that can modify the progression of the pathology,” he says. “I always tell my patients, ‘If I keep your brain working until you are done using it, and you drop dead of a heart attack, then I win and the cardiologist loses.’ ” EM

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Emory Medicine Summer 2010