New treatments for Alzheimer's showing promise

Drugs aim to disrupt cascade of damage in the brain

by Nicky Penttila

June 14, 2007

Researchers reported progress on several potential drug therapies for people with Alzheimer's disease  during the Alzheimer’s Association International Conference on Prevention of Dementia in Washington, D.C., this week. The drugs target different sections of the system that scientists suspect causes the progressive degeneration of brain tissue that leads to loss of memory, motor skills and life.  

"It was enormously encouraging to hear the reports at the meeting," said Marilyn S. Albert, Professor of Neurology and Director of the Division of Cognitive Neuroscience at Johns Hopkins University, on Tuesday, the final day of the conference. Albert spoke about the drugs and other progress in Alzheimer's research on Tuesday evening during a forum at the Dana Center. Still, she cautioned against over-optimism.

"We don't know that any of these drugs is the answer, or the partial answer," she said. All are in late-stage testing, from which on average one drug in three proves itself safe and effective. Most of the drugs have been in the works for a decade or more.  One, originally from Russia, was first used to relieve hay fever.

Three of the four drugs currently on the market for Alzheimer's were developed under the theory that it was the loss of the chemical neurotransmitter acetylcholine that was triggering the disease. These drugs improve function in people with the disease, but do not change the rate at which their function declines over time. This suggested that acetylcholine loss was not the cause of the disease, so researchers went back to the blackboard, the microscope and the brain-imagers to come up with another theory, Albert said.

New targets

The current working theory is that the overproduction and accumulation of amyloid beta, a byproduct of a natural process of breaking down proteins in the brain, triggers the cascade leading to Alzheimer's. Something happens in the system that causes too much amyloid to be made or that prevents it from being cleared away in the normal way; it starts to clump into amyloid plaques, killing cells and building more of itself.

Researchers over the past decade have discovered quite a bit about the basic mechanisms of Alzheimer's, Albert said, and drug developers have used their findings to target drugs to reduce or lower the production of amyloid beta (Abeta), stop its clumping or increase its clearance rate. Other drugs are considered adjuncts or co-therapies, easing problems such as inflammation and reduced energy in the brain.

Some of the therapies reported on this week:

  • Alzhemed (made by Neurochem): an Abeta lowering agent; researchers are evaluating completion of Phase 3 trial (Phase 3 compares the results of usually hundreds of people taking the new treatment with the results of people taking the standard treatment; testing safety and effectiveness)
  • AN1792 (Elan): a vaccine against Abeta; moving into Phase 3 trials
  • Flurizan (Myriad): inhibits the action of gamma secretase, and lowers Abeta; a Phase 3 trial is underway; results from extending treatment for 12 months after the end of the Phase 2 trial shows patients' symptoms appear stabilized
  • LY450132 (Lilly): also inhibits the action of gamma secretase; it is moving into a Phase 3 trial
  • Rosiglitazone (GlaxoSmithKline): improves mitochondrial function and reduces Abeta, it is most effective in people who have a particular variant of the ApoE gene; a Phase 3 trial is underway
  • AC-1202 (Accera): increases ketone bodies, providing energy to cells (is seen as a co-therapy); positive evidence from a Phase 2 trial (Phase 2 trials test whether a new treatment has the intended effect on its target)
  • Vitamin B (ADCS): a Phase 3 trial was negative overall but suggested that people with very mild Alheimer's may benefit
  • Dimebon (Medivation): inhibits cholinesterase, improves mitochondrial function; positive evidence in a Phase 2 trial showed stabilization of symptoms

"All these drugs are being applied in people who have AD," Albert said, people who already show an enormous amount of loss of function.  "When we begin to develop better treatments, we don't want to wait."

While current drugs can treat symptoms and slow the final decline for a while, the goal is to slow the development of full blown symptoms and, ideally, to prevent it altogether. Alzheimer's is a progressive disease; the changes in the brain start long before symptoms show and a diagnosis can be made. Scientists are working on new tests (including blood tests and brain scans) to diagnose the disease earlier, so people can start treatment earlier. But prevention would be best.

Alzheimer's is a complex disease, first affecting the hippocampus, a busy, tightly networked area of the brain. People's genetic makeup can offer clues that they might be at risk and that they might respond to one drug and not another. There is a lot still to learn, and the answers likely won't be simple or one-size-fits-all.

One model of treatment could be the way cancer is treated, with a "cocktail" of drugs, depending on one's risk factors, Albert said.

And because the prevalence of Alzheimer's is on the rise, preventive treatment, when discovered, would be a major health advance, she said. A model of that would be how heart disease is treated, with many people taking a daily aspirin and others a statin drug, depending on their genetics, family histories and other risk factors.

For progress, money and volunteers

Today, 5 million people in the United States have Alzheimer's. By 2030, the number is expected to increase to 7.7 million people; by 2050, 16 million will be affected, according to the Alzheimer's Association. Worldwide, one in 85 people will have Alzheimer's in 2050, if today's trends continue.

It is a costly disease, devastating to patients, their families and friends, their workplaces and national health-care systems. For example, Medicare spends three times more on clients with Alzheimer's than on those without, and per-patient costs are expected to double in the next decade.

Half the cost (and most of the time it takes) to develop drugs is spent doing the basic research. Most of that is funded by the federal government, which has not increased funding for the past few years, in effect cutting it as inflation continues to rise.

"We feel frustrated" about funding issues, Albert said. "We feel we're on the brink of finding better treatments at the very moment the funding is being reduced." 

Besides dollars, researchers and drug developers need bodies, in sickness and in health.

"To develop drugs, you need a lot of people to volunteer," Albert said. But recruiting has remained difficult. "So we need to change the culture a bit," she said, to "make people feel it's part of their responsibility to the next generation to participate in the clinical trials that will help us find better drugs."