MARCH / APRIL 2006

FORUM

Advances in knowledge and technology help move research aimed at curing Alzheimer's disease from the laboratory to the clinic

brain image

PET image showing amyloid plaques in the brain of an Alzheimer's patient

Alzheimer’s disease is among the most devastating conditions the world faces today—not just for those who lose their intellectual abilities, but for society as a whole. Alzheimer’s-related dementia slowly erodes memory, orientation, judgment, and reasoning and eventually takes the lives of its victims. Worldwide, it affects around one out of 20 people over age 65 and one in five over age 80. And as the number of elderly grows, the prevalence of Alzheimer’s disease is expected to rise dramatically, particularly in developing and heavily populated countries.

In addition to its social and emotional toll, Alzheimer’s is one of the world’s most costly health challenges. According to a recent report by researchers at the Huddinge University Hospital and Karolinska Institute in Stockholm, the worldwide cost of providing medical care for people who have Alzheimer’s-related dementias is between $129 and $159 billion each year.

Alzheimer’s has no known cure. But Alzheimer’s research is making tremendous headway, with information discovered in laboratories being translated into drug development and clinical trials. Advances in neuroimaging techniques and biological markers, and genetic and molecular findings are yielding clues about the origins and mechanisms of the disease. Recently these discoveries have laid the foundation for novel treatments that may one day slow Alzheimer’s disease or prevent it altogether.

New drugs, new era
“Over the past two to three years, the field has moved strongly into the clinic,” says Dennis Selkoe, MD, a professor of neurological diseases at Harvard Medical School and Brigham and Women’s Hospital whose groundbreaking work on the mechanism of Alzheimer’s has helped pave the way for today’s drug development. “After decades of investigation into the root causes of Alzheimer’s”, he says, “we have finally entered the era of disease-modifying treatment trials.”

Dennis Selkoe, MD

Dennis Selkoe: “Over the past two to three years, the field has moved strongly into the clinic. After decades of investigation into the root causes of Alzheimer’s, we have finally entered the era of disease-modifying treatment trials.”

Today, doctors often prescribe one or more of four FDA-approved drugs for treating Alzheimer’s disease. Three are cholinesterase inhibitors, which treat mild-to-moderate disease symptoms by slowing an enzyme that normally breaks down a neurotransmitter (acetylcholine) involved in forming memories. The fourth approved Alzheimer’s drug is an N-methyl-D-aspartate (NMDA)-antagonist, which lowers the effects of another neurotransmitter that can contribute to cognitive and behavioral symptoms in Alzheimer’s, and is generally prescribed for people with moderate or severe symptoms.

In addition to prescribing these drugs, doctors use a number of other drugs and psychological approaches to treat the behavioral problems that accompany Alzheimer’s disease as it progresses.

The problem with these current approaches is that they primarily address the symptoms of Alzheimer’s. New drugs in development have the potential to do much more. These medications target the underlying pathogenesis, the cause, of Alzheimer’s, and could possibly slow or stop the disease’s progression.

The new drugs are based on the discovery of a toxic small peptide, or protein, called beta-amyloid (Aß), and the gene mutations that cause it to accumulate in the brain. Beta-amyloid is a small piece of a larger protein called amyloid precursor protein, or APP, that extends from the inside to the outside of brain cells. APP is broken down (or “cut”) by several proteins called “secretases” that act as scissors. Alpha-secretase and gamma-secretase together cut APP into shorter fragments that are easily dissolved in the brain. When beta-secretase and gamma-secretase together cut APP, they produce longer fragments, called beta-amyloid 40 (Aß40) and beta-amyloid-42 (Aß42). Aß42 fragments are stickier than Aß40 fragments and that causes them to build up and combine with other fragments to form Alzheimer's plaques. Currently, Aß42 is thought to be the major culprit in Alzheimer’s-type dementia.

As the amount of Aß42 increases in the brain, it seems to collect in the synapses, or tiny spaces between adjacent nerve cells, short-circuiting communication. Initially, there’s little evidence of the interruption. But over a period of years, the Aß42 peptides clump like spaghetti and form larger amyloid plaques—the protein masses found in the brains of people with Alzheimer’s (see sidebar).

Selkoe says the drugs currently being tested in humans include antibodies that have the potential to clear Aß from the brain, enzyme inhibitors that prevent it from forming in the first place, and drugs that make it “less sticky” and therefore less likely to clump and disturb brain cells.

Clearing Aß from the brain
In a 31-center 180-person Phase II placebo-controlled trial, scientists are testing a humanized monoclonal antibody called AAB-001, which targets Aß and appears to decrease its accumulation in the brain, at least in preclinical animal models.

The antibodies (derived originally from a mouse but engineered to have much of the structure of a natural human antibody) are injected into a patient’s vein. From there they circulate throughout the plasma, and some make their way into the brain. When the antibodies see Aß, they “latch onto it,” explains Selkoe, apparently allowing the peptide to be “eaten by local scavenger cells.” Because the antibody is administered to the patient as such, rather than arising from an active vaccination that mobilizes the immune system, the process is referred to as “passive” immunotherapy.

A clinical trial of an “active” vaccine showed some encouraging results, but had to be stopped four years ago when six percent of the patients developed a brain inflammation (meningoencephalitis). Because the new approach doesn’t stimulate the body to produce its own antibodies, it is believed to carry less risk of triggering inflammation of the brain.

If the passive immunization approach succeeds, it would be the first vaccine for a chronic, noninfectious disease. This could have tremendous ramifications. Unlike passively administered antibodies, a vaccine only needs to be given once in a while. And to date, immunization for widespread diseases is the prevention approach that has been most successful in developing nations.

Lowering Aß levels
An investigational anti-amyloid drug called R-flurbiprofen (Flurizan) is entering a Phase III clinical trial. This drug modulates gamma-secretase, encouraging it to cut APP into fragments with 38 instead of 42 amino acids—thus lowering the production of the highly toxic Aß42.

Rudolph Tanzi

Rudolph Tanzi: Exploring the role played by a microscopic protein fragment called amyloid-beta (Aß)-protein in the development of Alzheimer’s disease

The results of Phase II trials were modest. The drug did not help people with mild and moderate Alzheimer’s disease when results for all 207 participants were considered as a whole. But when investigators looked at the data for just the 128 participants with mild Alzheimer’s, they found some stabilization (lack of worsening) on several tests of mental function. Based on these preliminary results, the company that makes the drug is recruiting people for a larger Phase III trial, involving around 100 U.S. sites and approximately 750 participants.

Another drug called NGX267, an M1 muscarinic agonist, is now in Phase I trials. This drug appears to lower Aß by binding to the same receptors as acetylcholine, effectively substituting for the neurotransmitter involved in memory formation, according to Rudolph Tanzi, MD, a professor of neurology at Harvard Medical School, and director of the Genetics and Aging Research Unit at Massachusetts General Hospital. This action, he says, promotes the “good” cleavage of APP by alpha-secretase and impedes the “bad” cleavage by beta-secretase.

Preventing Aß from clumping
Furthest along is a drug called Alzhemed, which launched its Phase III clinical trial in 2004. The treatment comprises a small organic molecule designed to bind to beta-amyloid peptides and keep the individual fragments from sticking together. The drug is expected to prevent the formation and deposition of amyloid fibrils (or clumps) in the brain and thereby slow the inflammatory response associated with the build-up of amyloid in people with Alzheimer’s disease. The drug is taken orally and was shown to be safe for people with Alzheimer’s disease in Phase II trials, according to the company that develops it. In addition, most of the participants who received the drug for up to 16 months reportedly showed stable cognitive function tests, especially those people with a mild form of the disease.

Another class of drugs called metal-protein attenuating compounds, or MPACs, is based on the 1994 discovery by Tanzi and colleagues that Aß requires copper and zinc to clump. The drugs are small molecules that attract these metals away from Aß, and thus impede aggregation. “They can also dissolve the aggregates that have already formed,” says Tanzi. The first version of the drug, PBT1, made it to Phase II trials with encouraging results, but the trials were stopped because of manufacturing problems. A more potent drug tested in animals, PBT2, is now in Phase I trials.

Old drugs, new application
While new drugs enter various phases of clinical trials, existing drugs are also being tested for use in Alzheimer’s patients, says Dr. Reisa Sperling, assistant professor of neurology at Harvard Medical School and Director of Clinical Research in the Brigham and Women’s Hospital’s Memory Disorders Unit. These drugs include cholesterol-lowering drugs (statins), non-steroidal anti-inflammatory drugs (NSAIDs), estrogen, vitamin B, and vitamin E. Of these, statins appear to hold the most promise, but the results of large randomized trials are still awaited.

Selkoe sounds a cautionary note about all of the trials mentioned above and others. “It is difficult, time-consuming, and expensive to test Alzheimer’s disease treatments in humans because it is a slow, chronic disease that varies greatly from patient to patient. And while there are millions of patients who have it, you have to follow them like a hawk during the trials,” he said. “It’s a lot of hard work to do it and there’s serious work left to be done before we know for sure if one or more of these drugs work. And even if there’s a hint of efficacy in one of the above approaches, it will still take Phase III studies in many hundreds of patients to get a drug approved.”

Despite these obstacles, Selkoe says he expects more clinical trial results to emerge within the next one to two years. And if they show signs of slowing or halting the disease progression, they are likely to precipitate a major shift in the way people think about Alzheimer’s disease and dementia. 

Disclosure: Dennis Selkoe and Rudolph Tanzi are both founders of pharmaceutical companies whose drugs are mentioned in this article.

 

 

Copyright 2006 Harvard Medical International

 

 

 

 

The amyloid hypothesis: From plaques to synapses
In Alzheimer’s disease, brain cells that process, store, and retrieve information degenerate and die. The question of why they die has been a source of much inquiry. Today, many scientists suspect that a microscopic protein fragment called amyloid-beta (Aß)-protein plays a significant role. 

“We’ve had a paradigm shift in terms of what we think causes Alzheimer’s disease,” says Rudolph Tanzi, a leading geneticist in the field. “We used to focus on amyloid plaques,” the large protein clumps that form outside of neurons in the brains of patients who have the disease. “But actually, it’s the key basic component of the amyloid plaque, the Aß42 peptide, that appears to be the bad guy. It may be wreaking havoc in the brain even before it gets lodged into plaques,” says Tanzi, whose lab played a key role in the discovery of the first three genes identified as culprits in early-onset Alzheimer’s disease.

According to the “amyloid (or Aß) hypothesis,” the plaques that have become the hallmark of Alzheimer’s disease are caused by flaws in the processes governing production, aggregation, or clearance of Aß42. Tanzi likens the process to an overflowing kitchen sink. “There are two reasons for the excess water,” he says. “Either the spigot is turned on too high, or the drain is clogged.” Similarly, a brain filling with amyloid plaques may be producing too much Aß or it may be producing normal amounts but is not effectively clearing the protein.

In the new paradigm, Tanzi argues that prior to being sequestered in plaques, Aß42 is interfering with the normal function of synapses, the connections between brain cells, thereby short-circuiting communication.

Novel molecules under investigation selectively lower Aß42, while not interfering with the necessary functions of gamma-secretase, which is necessary for clipping other molecules. Tanzi says he believes these drugs represent the most promising avenue of treatment for Alzheimer’s because they “nip the disease in the bud.”

In support of this new paradigm, Dennis Selkoe and his colleagues, as well as other laboratories, have found evidence that Aß42 may principally do its damage early on, when the clumps are in small soluble clusters called oligomers. These early-stage doublets and triplets (or dimers and trimers) of Aß42 appear to block an aspect of memory function, called long-term potentiation (LTP), which has been shown to be instrumental to learning and memory in animals.

“If the amyloid hypothesis is accurate, if we chronically treat people with drugs that target Aß-protein, we should stop the progression, and there might even be some repair mechanisms that would come into play.”

Besides paving the way for drug development, the amyloid hypothesis has continued to be supported by novel discoveries in genetic research on Alzheimer’s disease. “Nearly every single Alzheimer’s disease gene mutation we and others have found operates to increase the accumulation of Aß42 in the brain,” says Tanzi. So far, he and other genetic investigators around the world have found three genes carrying over 170 different Alzheimer’s disease-causing mutations associated with early-onset disease.