Using powerful new drug-screening technologies, researchers are identifying dozens, perhaps hundreds of possible targets for drugs aimed at preventing, treating, or slowing the progression of Alzheimer's disease (AD). Many of these compounds appear to work in animals with Alzheimer's-type dementia -- good news for little furry creatures.
But for the estimated 25 million people worldwide with Alzheimer's disease and other forms of dementia and the millions more who care for them, the news about drugs for Alzheimer's disease -- after the first blush of enthusiasm has faded -- has ranged from mildly promising to disheartening.
Perhaps it's a measure of how difficult the problem is that one of the biggest headlines from the 9th International Conference on Alzheimer's Disease and Related Disorders in Philadelphia came from a clinical trial of the drug Aricept. The drug appears to delay the onset of Alzheimer's disease in people with mild cognitive impairment by six to perhaps 18 months, according to researcher Ronald Petersen, MD, PhD, from the Mayo Clinic in Rochester, Minn. Mild cognitive impairment appears to set the stage for the development of Alzheimer's dementia.
There is no cure for Alzheimer's disease. The drugs used to treat the disease work to slow the progression of symptoms. Aricept works by preventing the breakdown of acetylcholine, a chemical used by the brain for memory and thinking. But studies have shown that the benefits of this treatment are short lived; by 18 months, patients who received Aricept had the same rate of progression to Alzheimer's disease as those who received a placebo.
Aricept is one many drugs used to treat Alzheimer's disease. It and medications such as Reminyl and Exelon are called cholinesterase inhibitors. In various studies, these drugs have shown small to modest improvements in memory and thinking skills in people with AD.
In April 2005, Reminyl's label was changed to include information about the deaths of 13 elderly patients who were taking the drug during a study. The deaths were due to various causes, including heart attack and stroke.
Another group of drugs, called NMDA receptor antagonists, have also shown minor improvements in mental function among patients with moderate to severe AD. These drugs work by controlling the levels of another chemical that is involved in processing and retrieving information.
Namenda is the only drug in this class approved for the treatment of moderate to severe AD. A recently published study showed that Namenda combined with Aricept allowed people with moderate to severe Alzheimer's disease to perform better in daily activities such as grooming, being left alone, and using the toilet. People receiving the drug combination also had a reduction in behavioral disturbances such as agitation and psychiatric symptoms that are among the most common causes of nursing-home placements among patients with AD. Studies presented at the current meeting also suggest that the drug is safe and effective at improving mental abilities and daily functioning.
New Approaches Needed
There are only five drugs approved by the FDA specifically for treatment of AD, and only four are widely used (the fifth, Cognex, has serious side effects and has largely fallen out of use). But because they work on the symptoms of Alzheimer's -- memory loss, confusion, agitation -- rather than on the actual pathology that causes the symptoms, these drugs may be a case of too little, too late.
"Everybody feels like we have to do something about this disease fast. The numbers of people who are going to be affected by it is so great, we know what a difference it could make if we could delay onset even by five years. And we also know that the disease takes a long time to evolve in the brain, so the sooner we intervene, the better," says Marilyn Albert, PhD, director of the division of cognitive neuroscience in the department of neurology at Johns Hopkins University School of Medicine in Baltimore.
The first brain changes of Alzheimer's disease may occur as early as 10 to 20 years before the first symptoms of the disease appear, Bengt Winbald, MD, PhD, professor of geriatric medicine and chief physician at the Karolinska University Hospital and Karolinska Institute in Stockholm, Sweden, tells WebMD.
Until recently, those changes have been too small or too subtle to easily detect, making it extremely difficult to identify people who could benefit from early intervention.
But that appears to be changing. A key theme at this year's Alzheimer's conference is advances in brain imaging that may make it possible to detect and diagnose early AD, leading to the development of drugs and other treatment strategies that could halt or at least slow the progression of disease.
Plaque Attacks and Tangled Webs
One of the most intriguing strategies discussed at this year's conference involves drugs or vaccines aimed at clearing deposits of an abnormal form of a protein that accumulates in the brains of people who suffer from Alzheimer's. The protein, known as beta amyloid, forms clumps or "plaques" and is a hallmark of Alzheimer's disease.
One experimental drug, called Alzhemed, has been shown in animal and human studies to clear significant amounts of beta amyloid deposits from the brain. A similar drug, known only as LY450139, has shown similar effects in humans.
Several companies are also working on vaccines that can stimulate the body to make antibodies that attack and dissolve beta-amyloid deposits. Other experimental drugs and vaccines are aimed at treating another suspected cause of AD, a different protein known as tau, which normally serves as a building block of nerves. In the brains of people with advanced AD, strands of twisted tau proteins, called fibrillary tangles, can be found inside brain cells.
But whether beta amyloid and tau are the causes of Alzheimer's disease or a result of it is still unclear.
"Clearly, beta-amyloid and tau pathology are part of the disease. The question is at what point in the cascade of events these things come into the picture," Alzheimer's disease research pioneer Zaven Khatchaturian, PhD, tells WebMD.
Khatchaturian, who is a consultant to other Alzheimer's disease researchers, formerly headed the Office of Alzheimer's Disease Research at the National Institute on Aging. He says that while it's encouraging that anti-amyloid therapies have gotten over the first hump -- safety in humans -- it's still unclear whether these therapies will have a positive effect on the disease itself.
Khatchaturian says instead of attacking late-stage features of the disease, it might be possible to intervene at an earlier step, before the normal brain protein known as amyloid precursor protein (APP) is transformed into the abnormal form beta amyloid.
"[APP] is a very significant protein in cell-to-cell communication. It's been around since the fruit fly, and there are different versions of it, but we don't have any idea about its function. One target may be that we're looking at the wrong end of the story, that the real story might be before it gets broken," Khatchaturian says.
Could Stem Cells Stem the Tide of AD?
Although human embryonic stem cells show promise for many neurological diseases such as Parkinson's disease, Huntington's chorea, spinal cord injuries, and other conditions, the complexity of Alzheimer's disease and the difficulty of delivering stem cells to the regions of the brain that are affected make them impractical for widespread use.
"Stem cells, although they're promising for other diseases, it's not very likely practically that they'll be used for Alzheimer's disease, because the way stem cell replacement is practiced in clinical research is by surgically implanting stem cells into regions of the brain where there has been degeneration, and that's fairly local in terms of Parkinson's disease and Huntington's, but for the entire cerebral cortex you're talking about making dozens of little holes in the skull," says Sam Gandy, MD, PhD, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia.
"There is a fairly new area focusing on identification of stem cells that are still present in the adult brain that weren't thought to be there," Gandy tells WebMD. "It's conceivable that if there were enough of those in quantity or you could deliver them, and if they have enough dividing potential you could stimulate them to replace the dying nerve cells in their immediate environment, but that still is very complicated."
The job would involve turning on dormant stem cells, getting them to change into the right kind of cell, and then getting them to move to the part of the brain where they're needed to repair damage, a series of tasks that are beyond our current capabilities, Gandy says.
Sheldon L. Goldberg, president and CEO of the Alzheimer's Association, tells WebMD that few or none of the 800 or so grant applications for research funding received by the association this year have been for stem cell research.
The State of Statins?
Observations that there appears to be an association between the use of cholesterol-lowering drugs known as statins and a lower incidence of Alzheimer's disease have prompted researchers to see whether these drugs could also help prevent it. As reported by WebMD, several studies presented at the conference here point to a link between heart disease risk factors and AD.
Statins also have anti-inflammatory effects that could be beneficial for Alzheimer's disease patients, and there is intriguing evidence indicating that the drugs may help to reduce the production of beta amyloid.
Yet to date, evidence about statins and Alzheimer's disease prevention has been mixed, and at least one study presented at the meeting suggests that the drugs may be less effective in people who have inherited a form of a gene that is associated with increased risk for AD and early-onset Alzheimer's.
"Whether eliminating the amyloid is going to eliminate the clinical picture, we don't know," Khatchaturian tells WebMD about current Alzheimer's disease research. "We have to start somewhere, but we may wind up with a big disappointment. That's science. There's no certainty. But compared to the amount of things we didn't know, compared to the total field of 10, 15, 20 years ago, I'm like a kid in a toy store."
Originally published July 23, 2004.
Medically updated April 6, 2005.