Alzheimer's Club

"ANN ARBOR, Mich. (AP) - The University of Michigan said Thursday that it has received a $10 million federal grant to support continued research into Alzheimer's disease. The National Institute on Aging, part of the National Institutes of Health, is awarding the five-year grant to the university's Michigan Alzheimer's Disease Research Center, the only such facility in Michigan and one of 33 nationwide. The new money will fund the center's Memory and Aging Project, a long-term study of memory, aging and dementia; laboratory research into a potential way to disable a protein believed to kill brain cells and trigger Alzheimer's symptoms; tests of new drugs and an experimental Alzheimer's vaccine; and efforts to encourage more minorities to participate in clinical studies. About 4.5 million Americans have Alzheimer's, a progressive form of dementia that usually starts among people in their 40s or 50s. Experts predict more than 10 million people will be diagnosed with the disease in the next 25 years.

"As the population gets older, the prevalence and cost of Alzheimer's disease will escalate, too," said Dr. Sid Gilman, director of the Michigan Alzheimer's Disease Research Center. "The total cost of the disease is estimated at $100 billion now, and that's conservative. Better treatment and prevention is urgently needed." The research center also is seeking older people who do not have memory loss or dementia to participate in comparative and to help researchers better understand the brain as it ages.

Researchers know that advancing age and a family history of dementia increases an individual's risk of developing Alzheimer's. But there is neither a cure for the disease nor reliable treatment for its symptoms, although a few medications that appear to help some patients have been approved for use. The Michigan research center has received federal funding since 1989. Its Memory and Aging Project has enrolled more than 1,000 state residents since then; researchers are following the progress of hundreds who are still alive."

Source: Detroit Free Press - Detroit,MI,USA (30 June 2005) [FullText]

"Emory University has received $7.4 million in federal funds for Alzheimer's disease research, university officials said Wednesday. The National Institute on Aging also designated the university as an Alzheimer's Disease Research Center, one of only 32 such designations it has made across the country.

The funding, distributed from the federal agency over five years, will help the university conduct research to better understand Alzheimer's disease and other neurodegenerative diseases, said Dr. Stuart Zola, associate director of Emory's Alzheimer's Disease Research Center. The center will study mild cognitive impairment, the transitional stage between healthy aging and dementia. In addition, it will examine how racial factors influence dementia.

The federal money is being matched by $700,000 from the Georgia Research Alliance, a private corporation created to support economic development in the state."

Source: Emory receives $7.4 million to study Alzheimer's disease. Associated Press (23 june 2005) [FullText] [Related article at Across Georgia]

"The media jumped all over the news from the Dementia Prevention Conference about a possible treatment for Alzheimer’s disease with the drug R-flurbiprofen (Flurizan) which is entering a Phase III clinical trial. The results so far, however, have been only mildly successful with the headlines on the Phase II study being “Flurizan Phase II Trial Shows No Overall Benefit.” Still, there is hope for this beta-amyloid altering drug being developed by Myriad Pharmaceuticals.

The Amyloid Hypothesis

[Dr.Koudinov: Make sure you did not miss coverage of the amyloid dogma by the Wall Steet Journal, and my letter to WSJ editor]

The "amyloid hypothesis" states that Alzheimer's disease is initiated by the production, aggregation and deposition of the toxic amyloid beta (Ab) peptide leading to disruption of cell-to-cell communication and eventually to the death of neurons in the brain.

The amyloid hypothesis remains the predominant scientific explanation for the cause of Alzheimer's disease and is the culmination of more than a decade of scientific research from around the world.

It has been discovered that the amyloid precursor protein, APP, is cleaved first by an enzyme called beta-secretase and is then cut into smaller fragments (amyloid peptides) by a second enzyme called gamma-secretase. These amyloid peptides are of several different lengths that have differing properties. Accumulation of the longer 42 amino acid form of this peptide (Ab42) causes cell death in the brain and initiates the formation of plaques, whereas shorter forms of the amyloid peptide are less toxic and do not initiate plaque deposits.

Some approaches to Ab42 reduction have been to block the activity of the gamma-secretase enzyme with drugs called "gamma-secretase inhibitors." This has led to safety concerns because many other essential proteins throughout the body are normally processed by gamma-secretase.

In contrast to the gamma-secretase inhibitor approach, Myriad scientists have pursued a different strategy to lowering Ab42 production and have selected the investigational compound Flurizan based on its ability to act as a modulator, rather than an inhibitor, of the gamma-secretase enzyme in cultured human cells and in animal models.

Insight as to how Ab42 may be implicated in Alzheimer's disease is the result of remarkable progress in Alzheimer's research that has occurred over the last two decades. Clinical trials are currently being conducted to develop drugs that will hopefully lead to disease-modifying therapies for this devastating disease.

Dementia is an umbrella term for many conditions, including Alzheimer's. Increasing age is currently considered the greatest risk factor for Alzheimer’s, with one in 10 of senior citizens over 65 and almost half of those over 85 affected. An estimated 4.5 million Americans have Alzheimer’s, which is twice as many as in 1980. By 2050, without gains in prevention, there could be as many as 16 million with the disease. Research has suggested it is the disease most feared by baby boomers and senior citizens.

Phase II trial shows that treatment with R-flurbiprofen (Flurizan) did not help individuals with mild or moderate Alzheimer’s disease when results for all 207 participants were considered as a whole, according to a report from Myriad, the drug’s developer.

However, the company says it saw some encouraging signs when data for just the 128 participants with mild Alzheimer’s were analyzed separately. Based on these preliminary results, Myriad plans to move forward with a Phase III trial and is recruiting participants throughout the United States.

In the Flurizan Phase III trial, about 100 U.S. sites will enroll approximately 750 individuals with mild to moderate Alzheimer’s disease. Participants will be randomly assigned to receive 400 or 800 milligrams of Flurizan twice daily or a placebo. The trial is designed to determine whether those assigned to either dose of Flurizan fare better in mental function or ability to carry out daily activities than those on the placebo. Trial details are posted in the federal online medical research database at ClinicalTrials.gov.

"We are pleased to hear that Myriad is sufficiently encouraged to go ahead with the Phase III trial," says William H. Thies, Ph.D., Alzheimer’s Association vice president, medical and scientific affairs. "R-flurbiprofen theoretically works by modifying beta-amyloid processing in a different way than most other drugs currently in clinical trials. It would be a worthwhile contribution to clinical knowledge to see how this drug performs in a larger trial designed to explore some of the early signs Myriad sees in their data.”

The company made a presentation of the details about their Phase II results at the Alzheimer’s Association International Conference on Prevention of Dementia in yesterday.

According to Myriad, the Phase II participants with mild Alzheimer’s who were taking the highest experimental dose of R-flurbiprofen showed a tendency to do better than those receiving the placebo on tests of memory and thinking skills, ability to carry out daily activities and overall function. However, those benefits did not meet statistical criteria for having a high likelihood of being due to the effects of the drug rather than to chance.

The company then further subdivided the data to focus on participants with mild Alzheimer’s taking the highest dose who also developed high levels of the drug in their bloodstream. That group experienced a statistically significant benefit in their ability to carry out daily activities and their overall function, but not on measures of memory and thinking skills.

Flurbiprofen is one of a handful of nonsteroidal anti-inflammatory drugs (NSAIDs) shown in laboratory and animal studies to reduce levels of beta-amyloid, a protein fragment considered a prime suspect in Alzheimer’s disease.

Generic flurbiprofen is a mixture of "R" and "S" molecules whose structures are mirror images of one another. Myriad’s Flurizan, also known by the investigational name MPC-7869, contains only R-flurbiprofen, the form that seems to have the greatest impact on beta-amyloid but has little or no anti-inflammatory effect. The anti-inflammatory effects of NSAIDs are associated with certain serious side effects, including bleeding in the stomach and intestines and increased risk of heart attack and stroke.

What the market thinks

In March, Decision Resources, Inc., one of the world's leading research and advisory firms focusing on pharmaceutical and health care issues, forecasts that the launches of Neurochem's Alzhemed and Myriad Genetics' Flurizan will be major factors in driving the market for the treatment of Alzheimer's disease to more than double to $4 billion by 2013.

According to the new Pharmacor study entitled Alzheimer's Disease, a dramatic change in market dynamics will begin half way through the study's 2003 to 2013 forecast period, as the first disease-modifying therapies—including Alzhemed (NC-531) and Flurizan (R-flurbiprofen)—enter the market. These two therapies will account for more than 56% of Alzheimer's disease treatment sales in the United States, Western Europe and Japan.

"Acetylcholinesterase inhibitors (AChEIs) will continue to dominate the Alzheimer's disease market until 2008, with the defining trend during this period being a shift in market share among competing AChEIs," said Michelle Grady, analyst at Decision Resources.

"Eisai/Pfizer's Aricept (donepezil) will retain its leadership position, as Shire/Janssen's Reminyl (galantamine) and, to a lesser extent, Novartis's Exelon (rivastigmine) gain market share. However, sales of these drugs will decline during the second half of the study period because of the expiry of their patents. All agents in this class will lose patent protection by 2013."

With the commercial launch of the biomarker Pittsburgh Compound B and the availability of disease-modifying drugs during the second half of the forecast period, the study also finds that physicians will begin diagnosing Alzheimer's disease earlier in the progression of the illness."

Source: Dementia Prevention Conference: Is Flurizan the Alzheimer's Treatment the World Awaits? Studies so far have shown modest results, new study underway. SeniorJournal.com (21 June 2005) [FullText]

"The first estimate of the worldwide direct costs of Alzheimer's disease and dementia care was released at the Alzheimer's Association International Conference on the Prevention of Dementia. As a result, scientists, advocates and those affected by the disease are calling for increased funding for research and support services.
A team led by Bengt Winblad, M.D., Professor of Geriatric Medicine and Chief Physician at the Karolinska University Hospital, Huddinge and the Karolinska Institutet, Stockholm, Sweden, estimated worldwide direct costs for dementia in 2003 at $156 billion (U.S.), based on a worldwide prevalence estimate of 27.7 million people with dementia.

"This study represents a significant step forward in confirming what we're up against," said William Thies, Ph.D., Alzheimer's Association vice president of Medical & Scientific Affairs. "Our choice is now clearer than ever. Either increase funding for Alzheimer's disease research to fend off this looming public health disaster, or sit back and wait for it to overwhelm the healthcare systems in the U.S. and throughout the world."

On Tuesday afternoon, researchers attending the Alzheimer's Association Prevention Conference will visit with members of Congress on the Hill to advocate for legislation such as the Ronald Reagan Alzheimer's Breakthrough Act. The bill, named after President Reagan who passed away from Alzheimer's in 2004, authorizes Congress to double federal funding for Alzheimer's disease research to $1.4 billion annually. It would also provide a tax credit up to $3,000 to help family caregivers pay for prescription drugs, home health and day care costs of caring for a loved one with Alzheimer's.

The worldwide costs of dementia were estimated from prevalence figures for the different regions and cost-of-illness studies from key countries. The researchers used a model based on the relationship between direct costs of care per demented individual and the gross domestic product (GDP) per capita in each country. As part of the research, several alternative calculation methods were explored and compared.

"It is of great interest for policy makers to have a view of how costs of dementia are distributed worldwide, and therefore we have tried to make a worldwide estimate," Winblad said. "Since detailed national data are lacking from many countries, we based our cost estimate on an assumed relationship between the GDP per capita and direct costs of dementia care. Such a relationship is known to be valid for overall costs of healthcare."

According to Winblad, the range in the study's sensitivity analysis was $129-159 billion (U.S.). Due to several sources of uncertainty, the range of cost estimates is relatively wide. However, the relative lack of precision should not obscure the fact that these are huge sums of money and, according to current population and prevalence estimates, these sums will continue to grow.

"Dementia care is a mix of formal and informal caregiving and this mix is not uniform throughout the world," Winblad said. "Even among the advanced economies there is a great range in how dementia care is provided, due to differences in family patterns, traditions, economic strength, care organization and financing. Nevertheless, it is obvious that the worldwide costs are substantial and the expected increase of elderly people, especially the anticipated rapid increase in developing countries, presents a great challenge for social and healthcare systems."

Currently, 92 percent of the total worldwide costs of dementia care were found in what the researchers termed "the advanced economies," which contain 38 percent of the prevalence..."

Source: Worldwide cost of Alzheimer's disease and dementia estimated at $156 billion. Medical Study News (21 June 2005) [FullText]

"WASHINGTON (19 June 2005) -- Advanced imaging technologies and novel biomarkers show great promise for earlier detection of Alzheimer's disease and dementia, as demonstrated by new research studies reported today at the first Alzheimer's Association International Conference on Prevention of Dementia in Washington.

"Earlier identification of Alzheimer's may enable earlier treatment and empower people to plan for their future sooner, including financial and legal matters," said William Thies, Ph.D., vice president, Medical and Scientific Affairs at the Alzheimer's Association. "Yet a large proportion of people with dementia are not diagnosed until the disease is in the moderate or advanced stages. As better treatments and prevention strategies emerge, this situation has to change. The Alzheimer's Association, the National Institute on Aging and industry are pushing hard for earlier detection and earlier intervention."

PET Scans May Predict Alzheimer's In Normal Elderly

Lisa Mosconi, Ph.D., and colleagues at the New York University School of Medicine examined 53 normal elderly subjects (age 67(plus or minus)8 years, range 50-84) who completed a longitudinal study using Positron Emission Tomography (PET) with fluoro-deoxyglucose (FDG) to study brain glucose metabolism. Glucose metabolism is the major energy source of the brain and is a sensitive indicator of brain damage. Subjects were followed for a period ranging from 10 to 24 years and had two or three PET scans. At the end of the study, six subjects had declined to Alzheimer's and 19 showed mild cognitive impairment (MCI).

At baseline of the study, reductions in glucose metabolism in the brain's hippocampus (Hip MRglc) were found for those study participants who would eventually decline to Alzheimer's or MCI, as compared to the non-decliners. Hip MRglc measurements taken at the beginning of the study predicted clinical outcome with a sensitivity of 83 percent for the Alzheimer's cases and 79 percent for the MCI cases. The follow-up Hip MRglc measures yielded equivalent prediction accuracy.

"This is the first brain imaging study to demonstrate detection of sporadic Alzheimer's disease in normal elderly subjects," Mosconi said. "This data suggests that the recognition of future Alzheimer's disease in a person who is cognitively normal is a realistic goal."

MR Spectroscopy May Show Presymptomatic Changes in Alzheimer's

Alison Godbolt of the Dementia Research Centre, Institute of Neurology, University College London, UK, and colleagues agreed with the widely held hypothesis that the biochemical and structural changes in the brain that eventually cause Alzheimer symptoms are actually present before memory loss begins.

To test this theory they examined seven people who were confirmed to have a gene mutation for early onset familial Alzheimer's disease (FAD), but were not yet showing any symptoms, and six healthy comparison subjects without Alzheimer's in the family. All 13 participants had a range of research tests, including MRS (magnetic resonance spectroscopy) brain scans. MRS scans are acquired in the same scanner as an MRI scan, but show levels of brain biochemicals rather than brain structure.

People who have a gene mutation for FAD are almost certain to develop Alzheimer's. The age at which they will develop symptoms can be predicted to some extent from the age at which other members of their family have developed the disease, which is often very similar in all sufferers in the family.

Using MRS, the researchers measured levels of two biochemicals that have previously been found to have altered levels in people with Alzheimer's: N-acetyl aspartate (NAA) and myo-inositol (MI). They measured these biochemicals in a region towards the back of the brain (the posterior cingulate) that is known to be involved in Alzheimer's.

MRS scans revealed different levels of the two brain biochemicals in the participants with the FAD gene mutations, when compared to the other subjects. NAA levels were reduced by statistically significant amounts. A borderline increase in MI levels was seen. The ratio of NAA to MI was reduced by a statistically significant amount. In addition, the size of the changes was related to how close participants were to the age when symptoms were predicted to start.

"Using MRS, we may be able to detect brain biochemical changes in healthy people who will later develop familial Alzheimer's, before their symptoms begin," Godbolt said. "Because this genetic form of Alzheimer's disease is rare and the number of participants in this study is relatively small, our findings must be confirmed with larger studies."

Plasma Beta-amyloid Levels As A Marker for Cognitive Decline, MCI and Alzheimer's

Rather than using advanced imaging technologies to examine the brain, Neill Graff-Radford, MBBCH, FRCP, of the Mayo Clinic Jacksonville, FL and colleagues analyzed plasma for levels of the beta-amyloid protein (AB) to determine if it is useful for identifying individuals at risk for Alzheimer's.

AB is normally present in blood and cerebrospinal fluid. Most AB is composed of 40 amino acids (AB40) but a small percentage has 42 amino acids (AB42). In people with Alzheimer's disease, AB42 forms plaques that are one of the pathological hallmarks of the disease.

The researchers followed 563 normal elderly volunteers (median age 78) for two to 12 years after blood was drawn for analysis of AB42 and AB40. At each visit, cognition was assessed using the Mattis Dementia Rating Scale (DRS), a 144-point cognitive test.

They found that subjects with low plasma AB42/AB40 ratios were at significantly greater risk for developing MCI or Alzheimer's, and they showed significantly greater cognitive decline as measured by the DRS. Subjects with plasma AB42/AB40 ratios in the lowest 25 percent of those studied had a significant three-fold increase in relative risk for MCI or Alzheimer's. Subjects in this group also developed MCI or Alzheimer's first, followed by those in the second 25 percent. MCI or Alzheimer's developed considerably later in subjects whose ratios were in the upper half.

"To develop and administer preventive therapy for Alzheimer's, it is essential to have markers that identify at-risk individuals in the same way that cholesterol levels are used to identify those at risk for heart disease," Graff-Radford said. "Our results indicate that the AB42/AB40 ratio may be a good biomarker for identifying normal elderly who will develop MCI or Alzheimer's in three to five years."

Screening for Dementia In Primary Care Settings

Recognizing that early detection of Alzheimer's disease is a work in progress, Henry Brodaty, AO, MB, BS, MD, FRACP, FRANZCP, Head of the Memory Disorders Clinic, Prince of Wales Hospital, Australia, and colleagues sought to determine the best currently available dementia screening instrument for general practitioners to use now.

"Primary care practitioners are the first port of call for people with progressive cognitive decline, and thus they are best situated to detect dementia early," Brodaty said. "Yet a large proportion of people with dementia are not being diagnosed until their disorder is advanced. One of several reasons cited by general practitioners for their failure to screen is the lengthy nature and inadequacies of current screening tools such as the Mini-mental State Examination (MMSE)."

The researchers located published research on the subject through the major medical databases, with 16 screening instruments included in the final review. They found that few of the screening tests had been tested in primary care or general population samples.

The researchers identified the General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, and Memory Impairment Screen (MIS) were most suitable for routine screening.

"The GPCOG, Mini-Cog, and MIS were all validated in community, population, or general practice samples, are easy to administer, and have administration times under five minutes," Brodaty said. "These instruments have negative predictive validities and misclassification rates at least as good if not better than the MMSE, but are quicker and easier to perform. We recommend that general practitioners adopt routine screening using the GPCOG, Mini-Cog, or MIS when patients are over age 75 or when cognitive impairment is suspected."

How Early Detection Impacts Individuals Being Diagnosed

According to Brodaty, what remains unclear is whether screening for dementia is beneficial. The topic raises many valid questions: Should everyone over a certain age have their cognitive status checked? What are the costs and benefits of earlier diagnoses? Is it ethical to screen for a condition for which we have no cure? What are the ramifications of diagnosing mild cognitive impairment? Is labeling deleterious? Does earlier pharmacotherapy with current medications really make a difference?

To begin to address these questions, Renee Beard, Ph.D., a National Institute on Aging Post-Doctoral Fellow in Gerontological Public Health at the Institute for Health Research and Policy, University of Illinois at Chicago, devoted 18 months to observing the diagnostic process, including observation and qualitative interviews with 50 people undergoing cognitive evaluation and focus groups with 35 individuals diagnosed with Alzheimer's or MCI.

Beard's data suggest that the experience of neuropsychiatric testing involves feelings of embarrassment, confusion, and alienation. Reactions to the diagnosis included shock, sadness, and fear, but also mixed emotions and relief to be able to give a name to their experiences of forgetfulness. After being diagnosed, individuals in the study tried to avoid being seen as defective by others. Strategies included using humor, being proactive, focusing on the positive, accepting help, and admitting their losses.

Diagnosed individuals said that there were positive aspects of being diagnosed, including having the time to plan for the future and focus on what is important to them, along with getting access to resources such as support groups and research studies. People in the study who were diagnosed in the earliest stages of memory loss were able to manage the symptoms of memory loss quite well.

"Although the disease involves many serious problems for diagnosed individuals and their families, Alzheimer's usually progresses slowly and there is typically a substantial time before a person needs assistance," Beard said. "During this period, how others interact with people who have been diagnosed is especially important."

"Early detection of Alzheimer's has granted researchers access to a population of people who are able to articulate their experiences and needs. By understanding the experiences of being tested and living with memory loss, we can significantly improve clinical practice. It is critical to continue exploring the individual, social, and bioethical consequences of increasingly earlier diagnoses," Beard said.

About the Alzheimer's Association

The Alzheimer's Association, the world leader in Alzheimer research and support, is the first and largest voluntary health organization dedicated to finding prevention methods, treatments and an eventual cure for Alzheimer's. For 25 years, the donor-supported, not-for-profit Alzheimer's Association has provided reliable information and care consultation; created supportive services for families; increased funding for dementia research; and influenced public policy changes.

The Alzheimer's Association's vision is a world without Alzheimer's and its dual mission is to eliminate Alzheimer's disease through the advancement of research and to enhance care and support for individuals, their families and caregivers. For more information, call (800) 272-3900 or visit http://www.alz.org/ .

Lisa Mosconi - Hippocampal Metabolism In The Longitudinal Prediction Of Decline From Normal Cognition To MCI And AD (funder: National Institutes of Health/National Institute on Aging) -- Alison Godbolt - MR Spectroscopy Demonstrates Presymptomatic Changes In Familial Alzheimer's Disease (funder: The Medical Research Council, UK) ; Neill Graff-Radford - Plasma AB Levels as a Premorbid Biomarker for Cognitive Decline, Mild Cognitive Impairment (MCI) and Alzheimer Disease (AD) (funders: National Institutes of Health/National Institute on Aging, and the Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program) -- Henry Brodaty - What is the Best Dementia Screening Instrument for General Practitioners to Use? (funder: New South Wales Department of Health) -- Renee Beard - Managing Memory Loss: How Early Detection Impacts Individuals Being Diagnosed (doctoral research)

Alzheimer's Association Contact: Alzheimer's Association media line, +1-312-335-4078,media@alz.org , or Prevention Conference press room, June 18-21,+1-202-745-2170

Source: New Research Studies Bring Early Detection of Alzheimer's Disease Closer to Reality. RedNova.com - Dallas, TX, USA (19 June 2005) [FullText]