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Category Archives: genetics

Alzheimer’s Disease Genetics Study

I want to alert you to an ongoing clinical trial that is designed to identify the genes that are responsible for causing Alzheimer’s Disease. This could be important to all of us who are predisposed to Alzheimer’s by birth. The investigators are searching for families with multiple incidences of Alzheimer’s disease. The study sponsored by the National Institute on Aging (NIA) is ambitious and they are seeking 3000 participants. They are recruiting nationally.

The purpose of the Alzheimer’s Disease Genetics Study is to identify the genes that are responsible for causing Alzheimer’s Disease (AD). One of the ways in which the risk factor genes for late onset AD can be investigated is by identifying and collecting genetic material from families with multiple members diagnosed with late onset AD (over 60 years of age).

You can read more about the study by visiting the clinical trials page or read more specifics of the study on the next page.

Related content Are you Genetically Predisposed to Alzheimer’s Disease?

Detailed Description:

The purpose of the Alzheimer’s Disease Genetics Study is to identify the genes that are responsible for causing Alzheimer’s Disease (AD). One of the ways in which the risk factor genes for late onset AD can be investigated is by identifying and collecting genetic material from families with multiple members diagnosed with late onset AD (over 60 years of age). Families meeting the criteria will have any two living family members diagnosed with AD with an onset of age 60 or older and at least one other affected or unaffected relative willing to participate. Families will be evaluated for a medical diagnosis and other factors. If eligible, blood samples will be collected from the participants to establish cell lines. If one of the identified family members is deceased, DNA will be extracted and stored from autopsy samples. Qualifying families will have a minimum of 3 members participating in the study: any two living family members diagnosed with AD with an onset at age 60 or older and a third member who must have an age of onset greater than 50, if affected, and 60 or older, if unaffected. The goal is to recruit 1,000 families in three years. This research will include a collection of samples from ethnic/minority populations and other special populations, including African Americans, the Amish, Hispanics, Asian Americans, and Japanese-Americans. Persons interested in registering to participate in this study can call the toll-free NCRAD number 1-800-526-2839 for more information. Local study sites are located all over the United States, and arrangements may be made for eligible families who do not live near a participating site.

Local sites, including the NIA-sponsored Alzheimer’s Disease Centers, will collect clinical and demographic data from these families, and the sites will send coded data (without identifiers) to the National Cell Repository for Alzheimer’s Disease (NCRAD) at Indiana University. The biological samples and data from these families will be available to qualified researchers, who must sign a Materials Transfer Agreement (to protect the privacy rights of participants in this study and to agree to share the results of genetic analyses) before receiving DNA and data. An oversight committee known as the Cell Bank Advisory Committee (CBAC) and the Coordinator of the NIA Alzheimer’s Disease Genetics Study, Richard Mayeux, MD, Columbia University, will review and monitor the process of family identification and enrollment, data collection, and the establishment of cell lines. This repository of DNA and cell lines was developed in hopes of discovering risk factor genes that contribute to late onset AD.

Eligibility
Genders Eligible for Study: Both
Accepts Healthy Volunteers: Yes

Contacts
Contact: Study Coordinator 1-800-526-2839
alzstudy@iupui.edu

More Information

NCRAD: the National Cell Repository for Alzheimer’s Disease

Responsible Party: National Cell Repository for Alzheimer’s Disease (NCRAD) ( Tatiana M Foroud )
Study ID Numbers: IA0042, NIH grant U24 AG21886
First Received: July 14, 2003
Last Updated: February 20, 2008
ClinicalTrials.gov Identifier: NCT00064870
Health Authority: United States: Federal Government

Original Content The Alzheimer’s Reading Room

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18-Month Phase III Trial Results for Tarenflurbil (Flurizan)

Unsuccessful phase III study does not mean the end of anti-amyloid therapies

Alzheimer’s Association International Conference on Alzheimer’s Disease 2008

Myriad Genetics (MYGN) announced on June 30, 2008, that its Phase III trial of tarenflurbil (Flurizan) had failed to achieve statistical significance on either of its two primary endpoints, and that the company was abandoning development of the compound for Alzheimer’s disease.

“While the results of the trial were certainly disappointing, just because the Flurizan Phase III clinical trial failed, doesn’t mean that other amyloid-targeted therapies in the clinical trial pipeline aren’t valid. We learn a great deal from every clinical study,” Gandy said. “There are many ways to impact amyloid and its role in Alzheimer’s. There are other drugs in development that target amyloid with mechanisms of action that are different from this one. One or more of these drugs may ultimately prove successful.”

At ICAD 2008, detailed data and results from the trial were presented for the first time by Robert C. Green, MD, MPH, of Boston University School of Medicine. Tarenflurbil is classified as a selective amyloid lowering agent, which was shown in nonclinical studies to modulate gamma secretase activity. The drug was in trials in people with mild Alzheimer’s to determine if its ability to lower the amount of toxic beta-amyloid would slow or stop the course of the disease.

In the randomized, double-blind, placebo-controlled trial, 1,649 individuals with mild Alzheimer’s (mean MMSE in both groups = 23.3) were randomized 1:1 to receive tarenflurbil 800 mg twice-a-day or placebo for 18 months. The co-primary outcome measures of efficacy were two standard measures of cognition and the ability to accomplish activities of daily living, respectively the ADAS-cog and the ADCS-ADL, with assessments conducted every three months. The secondary outcome measure was the Clinical Dementia Rating scale. Exploratory outcomes included the Neuropsychiatric Inventory (NPI), Quality of Life-Alzheimer’s test, and Caregiver Burden Inventory.

The researchers found that the drug did not achieve statistical significance in either of its primary endpoints of cognition and activities of daily living. Also, it did not achieve statistical significance on the secondary endpoint. By the end of the 18-month trial, patients in both the tarenflurbil and placebo groups had declined approximately seven points on the ADAS-cog scale and 10 points on the ADCS-ADL scale.

According to the researchers, the reported adverse effects reflect the expected profile of the elderly population with Alzheimer’s and, in most participants, symptoms were well balanced between the tarenflurbil and placebo groups. However, in the tarenflurbil treatment group, there was increased frequency of anemia (9.7 percent vs. 4.5 percent), infections (pneumonia, H. zoster, sepsis) (6.9 percent vs. 2.9 percent), and gastrointestinal ulcers (1.7 percent vs. 0.4 percent).

“This was the largest and longest placebo-controlled AD treatment trial ever completed,” Green said. “While the trial did not meet its endpoints, it was well-designed and executed, and it provided clear answers regarding Flurizan’s lack of efficacy and its safety.”

“The fact that both the drug-treated and placebo groups declined over the course of the trial – and that the placebo-treated patients declined at the expected rate – shows that we can do this type of trial in people with mild Alzheimer’s. As the first trial to ever study a large population of mild Alzheimer’s patients, we’ve collected very valuable data on the progression of the disease in its earliest stages. We are confident that the results of this study will help researchers in their quest to develop new and better treatments for Alzheimer’s,” Green added.

“This drug candidate, in this dose, in this group did not work. But, like much good science, the study raises as many questions as it does provide answers. Was the dose right? Was the study long enough? Did they start the intervention early enough in the course of the disease? Designing and executing clinical studies that answer these questions will help us defeat Alzheimer’s disease,” Gandy said. “The only way we are going to solve the problem of Alzheimer’s is for scientists and companies to have the courage to make significant investments in these large scale trials – which may or may not work. This was a very well done study and the company and scientists are to be commended for that.”

Myriad Genetics Reports Results of U.S. Phase 3 Trial of Flurizan™ in Alzheimer’s Disease

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Efficacy and safety of tarenflurbil in mild to moderate Alzheimer’s disease: a randomised phase II trial

We will try to keep you posted when the Phase 3 trial begins. Feel free to subscribe to our email list if you would like to be notified.

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800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD.


Source, Findings

A prespecified interaction analysis revealed that patients with mild AD (baseline MMSE 20–26) and moderate AD (baseline MMSE 15–19) responded differently to tarenflurbil in the ADAS-cog and the ADCS-ADL (p≥0·10); therefore, these groups were analysed separately. Patients with mild AD in the 800 mg tarenflurbil group had lower rates of decline than did those in the placebo group in activities of daily living (ADCS-ADL difference in slope 3·98 [95% CI 0·33 to 7·62] points per year, effect size [reduction from placebo decline rate] 46·4%, Cohen’s d 0·45; p=0·033) and global function (CDR-sb difference −0·80 [−1·57 to −0·03] points per year, effect size 35·7%, Cohen’s d 0·42; p=0·042); slowing of cognitive decline did not differ significantly (ADAS-cog difference −1·36 [−4·07 to 1·36] points per year, effect size 33·7%, Cohen’s d 0·20; p=0·327). In patients with moderate AD, 800 mg tarenflurbil twice per day had no significant effects on ADCS-ADL and ADAS-cog and had a negative effect on CDR-sb (−52%, Cohen’s d −1·08; p=0·003). The most common adverse events were diarrhoea (in seven, nine, and five patients in the 800 mg, 400 mg, and placebo groups, respectively), nausea (in seven, seven, and four patients), and dizziness (in five, nine, and four patients). Patients with mild AD who were in the 800 mg tarenflurbil group for 24 months had lower rates of decline for all three primary outcomes than did patients who were in the placebo group for months 0–12 and a tarenflurbil group for months 12–24

Interpretation

800 mg tarenflurbil twice per day was well tolerated for up to 24 months of treatment, with evidence of a dose-related effect on measures of daily activities and global function in patients with mild AD.

Funding
Myriad Pharmaceuticals.

 

PARADE Magazine Features Smart Genetics and Alzheimer’s Mirror

clipped from www.breitbart.com


Magazine urges readers to participate in nationwide poll on Alzheimer’s genetic testing

Smart Genetics has announced that PARADE magazine is featuring Alzheimer’s Mirror as part of a nationwide poll asking readers if they want to learn their risk level for developing Alzheimer’s disease. To vote, visit: http://www.parade.com/articles/editions/2008/edition_03-30-2008/Intelligence_Report#health.

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Alzheimer’s Risk Higher for Kids When Both Parents Stricken

clipped from blogs.wsj.com

Children whose parents both have Alzheimer’s disease are at a greater risk for developing the degenerative brain disorder, according to the results of a study that appears today in the Archives of Neurology.

The researchers found patients though a registry at the University of Washington Alzheimer’s Disease Research Center. Jayadev told us that while this is the largest group of offspring with two Alzheimer’s parents studied, the number of patients remains small.

It might be common sense anyway, but children of two parents with Alzheimer’s should take extra care of themselves. Suman Jayadev, lead author of the study and a neurologist at the University of Washington in Seattle told us, “If you are at an increased risk, you should be that much more aware of keeping good health, exercising and eating right. We’re all at risk for this, but these people may be at higher risk.”

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Posted by on March 11, 2008 in alzheimer's, bob demarco, genetics

 

Unraveling Alzheimer’s secrets

clipped from www.telegram.com

Kerley, 52, has spent much of her life in the shadow of an illness that gradually destroys memory, personality and the ability to think, speak and live independently. Her mother, grandmother and a maternal great-aunt all developed Alzheimer’s disease. Her mother, 78, is in a nursing home in the advanced stages of dementia, helpless and barely responsive.

Currently, the diagnosis is not made until symptoms develop, and by then it may already be too late to rescue the brain.

A radioactive dye called PIB (for Pittsburgh Compound B) has made it possible to use PET scans to find deposits of amyloid, an Alzheimer’s-related protein, in the brains of live human beings.

It may lead to earlier diagnosis, help doctors distinguish Alzheimer’s from other forms of dementia

“PIB is being used today to help determine whether drugs that are meant to prevent or remove amyloid from the brain are working, so we can find drugs that prevent the underlying pathology of the disease.”

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Unraveling Alzheimer’s secrets

Scientists searching for ways to detect disease early

By Denise Grady
The New York Times

For a perfectly healthy woman, Dianne Kerley has had quite a few medical tests in recent years: MRI and PET scans of her brain, two spinal taps and hours of memory and thinking tests.

Kerley, 52, has spent much of her life in the shadow of an illness that gradually destroys memory, personality and the ability to think, speak and live independently. Her mother, grandmother and a maternal great-aunt all developed Alzheimer’s disease. Her mother, 78, is in a nursing home in the advanced stages of dementia, helpless and barely responsive.

“She’s in her own private purgatory,” Kerley said.

Kerley is part of an ambitious new scientific effort to find ways to detect Alzheimer’s disease at the earliest possible moment. Although the disease may seem like a calamity that strikes suddenly in old age, scientists now think it begins long before the mind fails.

“Alzheimer’s disease may be a chronic condition in which changes begin in midlife or even earlier,” said Dr. John C. Morris, director of the Alzheimer’s Disease Research Center at Washington University in St. Louis, where Kerley volunteers for studies.

Currently, the diagnosis is not made until symptoms develop, and by then it may already be too late to rescue the brain. Drugs now in use temporarily ease symptoms for some, but cannot halt the underlying disease.

Many scientists believe the best hope of progress, maybe the only hope, lies in detecting the disease early and devising treatments to stop it before brain damage becomes extensive. Better still, they would like to intervene even sooner, by identifying risk factors and treating people preventively – the same strategy that has markedly lowered death rates from heart disease, stroke and some cancers.

So far, Alzheimer’s has been unyielding. But research now under way may start answering major questions about when the disease begins and how best to fight it.

A radioactive dye called PIB (for Pittsburgh Compound B) has made it possible to use PET scans to find deposits of amyloid, an Alzheimer’s-related protein, in the brains of live human beings. It may lead to earlier diagnosis, help doctors distinguish Alzheimer’s from other forms of dementia and let them monitor the effects of treatment. Studies with the dye have already found significant deposits in 20 percent to 25 percent of seemingly normal people over 65, suggesting that they may be on the way to Alzheimer’s, though only time will tell.

“PIB is about the future of where Alzheimer’s disease needs to be,” said Dr. William E. Klunk, a co-discoverer of the dye at the Alzheimer’s research center at the University of Pittsburgh. “PIB is being used today to help determine whether drugs that are meant to prevent or remove amyloid from the brain are working, so we can find drugs that prevent the underlying pathology of the disease.”

Though PIB is experimental now, studies began in November that are intended to lead to government approval for wider use.

Currently, for the most common form of Alzheimer’s disease, which occurs after age 65, there is no proven means of early detection, no definitive genetic test. But PIB tests might be ready before new treatments emerge, making it possible to predict who will develop Alzheimer’s – without being able to help.

Researchers are also using MRI scans to look for early brain changes, and testing blood and spinal fluid for amyloid and other “biomarkers” to see if they can be used to predict Alzheimer’s or find it early.

Studies of families in which multiple members have dementia are helping to sort out the genetic underpinnings of the disease.

Finally, experiments are under way to find out whether drugs and vaccines can remove amyloid from the brain or prevent its buildup, and whether doing so would help patients. The new drugs, unlike the ones currently available, have the potential to stop or slow the progress of the disease. At the very least, the drug studies will be the first real test of the leading theory of Alzheimer’s, which blames amyloid for setting off a chain of events that ultimately ruin the brain.

Alzheimer’s was first recognized 100 years ago, and in all that time science has been completely unable to change the course of the disease. Desperate families spend more than $1 billion a year on drugs approved for Alzheimer’s that generally have only small effects, if any, on symptoms. Patients’ agitation and hallucinations often drive relatives and nursing homes to resort to additional powerful drugs approved for other diseases such as schizophrenia, drugs that can deepen the oblivion and cause severe side effects such as diabetes, stroke and movement disorders.

Alzheimer’s is the most common cause of dementia (artery disease, Parkinson’s and other brain disorders can also lead to dementia). Five million people in the United States have Alzheimer’s, most of them over 65. It is the nation’s sixth leading cause of death by disease, killing nearly 66,000 people a year and probably contributing to many more deaths. By 2050, according to the Alzheimer’s Association, 11 million to 16 million Americans will have the disease.

“Sixteen million is a future we can’t countenance,” said William H. Thies (pronounced thees), the association’s vice president for medical and scientific relations. “It will bankrupt our health care system.”

The costs are already enormous, $148 billion a year – more than three times the cost of chronic lung disease, even though Alzheimer’s kills only half as many people.

To a great extent, increases in dementia are the price of progress: More and more people are living long enough to get Alzheimer’s, some because they survived heart disease, strokes or cancer. It is a cruel tradeoff. The disease is by no means inevitable, but among people 85 and older, about 40 percent develop Alzheimer’s and spend their so-called golden years in a thicket of confusion, ultimately becoming incontinent, mute, bedridden or forced to use a wheelchair and completely dependent on others.

“It makes people wonder whether they really want to live that long,” Klunk said.

The potential market for prevention and treatment is enormous, and drug companies are eager to exploit it. If a drug could prevent Alzheimer’s or just reduce the risk, as statins such as Lipitor do for heart disease, half the population over 55 would probably need to take it, Thies said.

If new drugs do emerge, they will come from studies in patients who already have symptoms, Thies said. But he said the emphasis would quickly shift to treating people at risk, before symptoms set in. Many researchers doubt that even the best preventive drugs will be able to heal the brains of people who are already demented.

Researchers are especially eager to study people like Kerley, because the children of Alzheimer’s patients have a higher-than-average risk of dementia themselves, and tracking their brains and minds may open a window onto the earliest stages of the disease.

 

Myriad Genetics Presents Mathematical Comparison of Disease Modification Trial Designs at Alzheimer’s Conference (MYGN)

Current Flurizan™ Phase 3 Study Design May Demonstrate Disease Modification (Alzheimer’s)

“We are excited about this persuasive mathematical comparison of clinical trial designs,” said Adrian Hobden, PhD, President of Myriad Pharmaceuticals, Inc. “We believe that this mathematical proof, coupled with the Flurizan trial design may strengthen the Company’s position with the FDA in favor of a disease modification label for Flurizan.”


Salt Lake City, UT, Jun 11, 2007—Myriad Genetics, Inc. (NASDAQ: MYGN) (www.myriad.com) announced today that it presented a mathematical comparison of a “Staggered Start” and a “Randomized Withdrawal” clinical trial design with a “Natural History Staggered Start” clinical trial design at the Alzheimer’s Association Prevention Conference held June 9 – 12, 2007, in Washington, D.C. The analysis demonstrates that the “Natural History Staggered Start” trial design currently being used in the Flurizan Phase 3 study can provide the same level of disease modification support as the cross-over trial designs, which are challenged by ethical concerns, dropout bias and complications.

A disease modifying therapy for Alzheimer’s disease (AD) is one that has an impact on the underlying pathology of the disease and thus slows the rate of a patient’s decline over the course of long-term treatment. In contrast, the currently available AD medicines are believed to treat the symptoms of AD without impacting the underlying disease process or providing long lasting benefit. The development of robust methods to demonstrate disease modification in AD clinical trials has been a controversial issue in the field, and to date, there have been no studies that provide convincing evidence of disease modification in AD. Two clinical trial designs that could provide evidence for disease modification were originally proposed for AD studies over 10 years ago by Paul Leber, then the head of the Division of Neuropharmacological Drug Products of the FDA. These designs have come to be known as the “Randomized Withdrawal” and “Staggered Start” designs and are based on measuring clinical outcomes in a cross-over type study.

In the randomized withdrawal design, patients are withdrawn from therapy after a defined period to determine whether the long-lasting benefit to the patient is maintained, demonstrating disease modification, or if the patient drops back to the level of patients on placebo for the duration of the study. In a staggered start design, one group of patients receives the active study drug for the entire study period, while a second group initially receives placebo and then later is given the active drug. If the second group fails to “catch up” in the level of performance of the first group, this is taken to be evidence for a disease modifying effect of the drug. Unfortunately, these designs are difficult to implement and have rarely been used in clinical trials as they are complicated by very long study durations, leading to high dropout rates that introduce biased results, as well as presenting ethical concerns unacceptable to patients and their families.

A team of biostatisticians and mathematicians at Myriad, led by Suzanne Hendrix, Ph.D., Sasha Gutin, Ph.D., and Scott Horton, has proposed an alternative strategy designated the “Natural History Staggered Start” analysis, that compares the slopes of decline of drug treated patients with those of patients receiving placebo and corrects for the severity of disease at baseline. The mathematical analysis presented at the Alzheimer’s Association AD Prevention Conference demonstrates that this trial analysis methodology is mathematically equivalent to the “Staggered Start” and “Randomized Withdrawal” designs and provides the same level of evidence of a disease-modifying drug effect in a clinical trial that is not subject to the above-mentioned complications, bias and ethical challenges of the previous designs.

“We are excited about this persuasive mathematical comparison of clinical trial designs,” said Adrian Hobden, PhD, President of Myriad Pharmaceuticals, Inc. “We believe that this mathematical proof, coupled with the Flurizan trial design may strengthen the Company’s position with the FDA in favor of a disease modification label for Flurizan.”

About Flurizan™
Myriad has two Phase 3 trials of Flurizan ongoing in patients with mild Alzheimer’s disease. In each study, participants are taking 800 mg of Flurizan or placebo twice daily, and participants enrolled will have taken the study drug for 18 months. Flurizan is the first in a new class of drug candidates known as Selective Amyloid beta-42 Lowering Agents (SALAs). Flurizan lowered levels of Abeta42 in cellular assays and animal models. Abeta42 is the primary constituent of senile plaque that accumulates in the brain of patients with Alzheimer’s disease. It is thought to be the key initiator of Alzheimer’s disease, since Abeta42 has the greatest tendency to aggregate, cause neuronal damage and initiate amyloid deposits in the brain. Most genetic mutations that cause early-onset Alzheimer’s disease appear to do so by increasing production of Abeta42. Myriad believes that Flurizan is the most advanced drug candidate that modifies the production of Abeta42 to be evaluated in a clinical trial for the treatment of Alzheimer’s disease.

About Myriad
Myriad Genetics, Inc. is a biopharmaceutical company focused on the development and marketing of novel healthcare products. The Company develops and markets molecular diagnostic products, and is developing and intends to market therapeutic products. Myriad’s news and other information are available on the Company’s Web site at http://www.myriad.com. Flurizan is a trademark of Myriad Genetics, Inc. in the United States and other countries.

This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include whether the Flurizan Phase 3 study design may demonstrate disease modification; the Company’s use of the Natural History Staggered Start trial design and trial analysis methodology in its Flurizan Phase 3 clinical trials; the ability of the Natural History Staggered Start trial design and trial analysis methodology to provide the same level of disease modification support as the cross-over trial designs; the ability of the Natural History Staggered Start trial design and trial analysis methodology to demonstrate that this trial analysis methodology is mathematically equivalent to the “Staggered Start” and “Randomized Withdrawal” designs and provides the same level of evidence of a disease modifying drug effect in a clinical trial that is not subject to the complications, bias and ethical challenges of previous designs; the excitement of the Company about this persuasive mathematical comparison of clinical trial designs and the Company’s belief that this mathematical proof, coupled with the Flurizan trial design, may strengthen the Company’s position with the FDA in favor of a disease modification label for Flurizan; the successful completion of the ongoing Flurizan Phase 3 trials; and whether the Flurizan Phase 3 trials results will demonstrate or support a claim of disease modification. These forward-looking statements are based on management’s current expectation and are subject to certain risks and uncertainties that could cause actual results to differ materially from those set forth or implied by forward-looking statements. These include, but are not limited to, uncertainties as to the extent of future government regulation of Myriad Genetics’ business; uncertainties as to whether Myriad Genetics and its collaborators will be successful in developing, and obtaining regulatory approval for, and commercial acceptance of, therapeutic compounds; the risk that markets will not exist for therapeutic compounds that Myriad Genetics develops or if such markets exist, that Myriad Genetics will not be able to sell compounds, which it develops, at acceptable prices; and the risk that the Company will not be able to sustain revenue growth for its predictive medicine business and products. These and other risks are discussed under the heading “Risk Factors” contained in Item 1A in our Annual Report on Form 10-K for the year ended June 30, 2006, which has been filed with the Securities and Exchange Commission, as well as any updates to those risk factors filed from time to time in our Quarterly Reports on Form 10-Q or Current Reports on Form 8-K. All information in this press release is as of the date of this release, and Myriad undertakes no duty to update this information unless required by law.

Contact:
William A. Hockett
EVP, Corporate Communications
(801) 584-3600





 
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Posted by on June 12, 2007 in alzheimer's, genetics, myriad

 
 
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