Benefits Aside, Phase 3 Alzheimer's Drug Increases Toxic Beta Amyloid in the Brain

by Rajashri on Jul 16 2009 9:20 PM

A Phase III Alzheimer's drug targeting two abnormal brain proteins, beta amyloid and phosphorylated tau, does offer some benefits, according to research reported today at the Alzheimer's Association 2009 International Conference on Alzheimer's Disease (ICAD 2009) in Vienna.

Scientists also reported on how clinicians view and treat mild cognitive impairment (MCI), a research category used to define the state between normal aging and Alzheimer's, that is now being used widely in clinical practice.

"There are now more than 5 million people living with Alzheimer's disease in the United States. The cost of caring for people who now have Alzheimer's, and those who will get it in the next few years, will bankrupt the healthcare system and devastate Medicare and Medicaid," said Ralph Nixon, PhD, MD, vice chair of the Alzheimer's Association Medical & Scientific Advisory Council.

"But, as these studies and many hundreds more reported at ICAD 2009 show, there is hope. There are currently dozens of drugs in Phase II and III clinical trials for Alzheimer's. This, combined with advancements in diagnostic tools, has the potential to change the landscape of Alzheimer's in our lifetime. How fast we get there depends completely on the investment in research. We need more government and private dollars for Alzheimer's research now to capitalize on the progress we've made in the last decade," Nixon added.

Surprisingly, Dimebolin Increases Brain Beta Amyloid in Alzheimer's Mouse ModelsRecent evidence suggests that dimebolin (Dimebon®, Medivation) may improve cognitive function in aged rodents and in people suffering from mild to moderate Alzheimer's, but how the drug produces these benefits remains unclear.

Samuel Gandy, MD, PhD, Mount Sinai Professor in Alzheimer's Disease Research; Professor of Neurology and Psychiatry; and Associate Director, Alzheimer's Disease Research Center at the Mount Sinai School of Medicine, New York, and colleagues John Cirrito PhD, and David M. Holtzman, MD, Professor and Chairman of the Department of Neurology at Washington University in St. Louis, MO, conducted a series of experiments in cells and in Alzheimer's mouse models to assess the effects of dimebolin on beta amyloid and other brain proteins known to be related to Alzheimer's disease.

Beta amyloid is a protein that is the main constituent of amyloid plaques found in the brains of people with Alzheimer's disease. It is widely considered a key player in the development and progression of Alzheimer's. The goal of anti-amyloid drugs that are currently in clinical trials is to reduce beta amyloid levels in the brain.

In a surprising result, the researchers at Washington University in St. Louis found that treatment with dimebolin caused an acute increase in brain beta amyloid levels in the animal models.

"This result is highly unexpected in what may prove to be a clinically beneficial Alzheimer's drug," Gandy said. "We need more research to further clarify how dimebolin affects beta amyloid levels in the brain."

"A number of ideas need to be pursued. It may turn out that the drug works by getting toxic amyloid out of brain nerve cells. Or, the effects of dimebolin on other brain systems may override its effect on increasing beta amyloid. Finally, the drug's beneficial actions might have nothing to do with amyloid, which, if true, indicates the existence of important therapeutic targets independent of beta amyloid," Gandy added.

The researchers note that so far they only studied acute systems, and it is conceivable that the chronic effect of dimebolin could be amyloid-lowering.

Immunotherapy Against Tau Tangles in Alzheimer's Mouse ModelsImmunotherapy (treatment by inducing, enhancing, or suppressing an immune response) targeting beta amyloid is being researched widely by companies and academics as a therapeutic option for Alzheimer's disease. Earlier, late stage, anti-amyloid immunotherapy trials in people were complicated, and eventually stopped, when about six percent of participants developed brain inflammation. Current trials in this area are working in a variety of ways to eliminate this side effect.

Tau tangles, the other major Alzheimer's brain pathology, are now also receiving attention as a target for immunotherapy. Also known as neurofibrillary tangles (NFTs), these lesions consist of an abnormal folded protein (phosphorylated tau), and research shows their accumulation in the brain is more closely associated with the progression of Alzheimer's symptoms than amyloid.

Building on previous studies using this approach (for example, Asuni et al. (2007)), Hanna Rosenmann, Ph.D., head of the Laboratory of Molecular Neurogenetics, Department of Neurology, Hadassah University Hospital, Ein Kerem, and an Investigator (Associate-Senior Lecturer) at the Hebrew University Hadassah School of Medicine, Jerusalem, Israel, and colleagues performed immunization studies against tau tangle pathology by immunizing NFT mice with a mixture of three phosphorylated-tau peptides (shortened versions of the full length tau protein that are phosphorylated like the NFTs). Previous experiments by this lab with non-phosphorylated full length tau caused brain inflammation in the animal models.

The researchers observed a robust decrease in the number of tau tangles in the brains of the mice immunized with the phosphorylated tau-peptides (~40%; p< 0.001), and detected anti-phosphorylated-tau antibodies in mouse serum. They found no evidence or symptoms of brain inflammation in the immunized mice.

According to Rosenmann, the decrease in tau tangles observed by her team is in accord with previous findings by Asuni's group, though Asuni immunized with a different phosphorylated tau peptide and immunization protocol.

"We believe that these results point to the therapeutic potential of phosphorylated-tau-immunotherapy in Alzheimer's," Rosenmann said. "We devoted significant effort to address not only the anti-tangle effect but also safety of a phosphorylated-tau vaccine. This was done in order to identify early in the preclinical stage any potential hazard of this potential Alzheimer's therapy."

Neurologists Views MCI as a Useful Clinical Diagnosis – Practice Guidelines Are NeededMild cognitive impairment (MCI) is a category of cognitive status that is used in research to define the state between normal aging and Alzheimer's, and it is now entering clinical practice. Little is known about how it is being used by clinicians or how they view the benefits and limitations of MCI as a clinical category.

In MCI, a person has problems with memory, language, or another mental function severe enough to be noticeable to other people and to show up on tests, but not serious enough to interfere with their daily life. Because the problems do not interfere with daily activities, the person is not diagnosed with Alzheimer's or another dementia. The best-studied type of MCI involves a memory problem and is called "amnestic MCI."

Research has shown that people with MCI have an increased risk of developing Alzheimer's over the next few years, especially when their main problem is memory. However, not everyone diagnosed with MCI goes on to develop Alzheimer's. There is currently no treatment for MCI approved by the FDA. Numerous clinical trials are investigating treatments to delay or prevent Alzheimer's in MCI populations.

Scott Roberts, PhD, Assistant Professor of Health Behavior & Health Education at the University of Michigan's School of Public Health; Jason Karlawish, MD, Associate Professor of Medicine and Medical Ethics with tenure, Senior Fellow of the Center for Bioethics and the Leonard Davis Institute of Health Economics, and Associate Scholar at the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania; and colleagues sought to assess how neurologists are diagnosing and treating patients with mild cognitive symptoms and how they view MCI as a clinical diagnosis. They surveyed members of the American Academy of Neurology (AAN) who had indicated a clinical practice focus on aging/dementia or behavioral neurology in a recent AAN Member Census using mail, fax and the Internet.

420 clinicians (response rate=48%) completed the survey. 88% reported at least monthly encounters with patients experiencing mild cognitive symptoms. Most respondents recognize MCI as a clinical diagnosis (90%) and use its diagnostic code for billing purposes (70%). When seeing this population, most respondents report routinely making recommendations for monitoring and follow-up (88%), counseling patients on physical (78%) and mental exercise (75%), and communicating about risk of dementia (63%).

Most respondents (70%) prescribe cholinesterase inhibitors at least sometimes for this population, with memantine (39%) and "other" agents (e.g., vitamin E, gingko) prescribed less frequently. Cholinesterase inhibitors and memantine are FDA-approved drugs for Alzheimer's. Relatively few respondents routinely provide information on support services (27%) or a written summary of findings (15%).

Respondents endorsed several benefits of making a clinical diagnosis of MCI:
  1. Labeling the problem is helpful (91%)
  2. Involving the patient in planning for the future (87%)
  3. Motivating the patient's risk reduction activities (85%)
  4. Helping the family with financial planning (72%)
  5. Prescribing medications useful for treating MCI (65%)

Some respondents noted potential drawbacks of MCI as a clinical diagnosis, including:
  1. It is too difficult to diagnose accurately or reliably (23%)
  2. It is usually better described as early AD (21%)
  3. A diagnosis can cause unnecessary worry (20%)

"Our results show that neurologists regularly see and treat people with MCI, despite the fact that the medications they are prescribing are not FDA-approved for this particular diagnostic category," Roberts said. "Clinicians vary greatly in the education and support they provide or recommend for people with MCI, suggesting that there is a need for practice guidelines in this area. Millions of people can be classified as having MCI, and these numbers are expected to rise in coming years. It is important to establish professional consensus about appropriate care for this population."

According to Roberts, the AAN is currently engaged in an evidence-based medicine review of the literature to develop a new practice parameter for MCI.