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Celera Discovers Gene Variants Strongly Associated with Alzheimer's Disease; Findings Could Lead to New Diagnostics and Targeted Therapeutics.



ROCKVILLE, Md. -- Research Published in Human Molecular Genetics Human Molecular Genetics is a semimonthly scientific journal published by The Oxford University Press.

See: Official Site
 and Presented at the International Conference on Alzheimer's Disease Alzheimer's disease (ăls`hī'mərz, ôls–), degenerative disease of nerve cells in the cerebral cortex that leads to atrophy of the brain and senile dementia.  in Madrid, Spain

Celera Genomics (NYSE NYSE

See: New York Stock Exchange
:CRA See Community Reinvestment Act. ), an Applera Corporation business, today announced the publication of data from its research studies showing that variants in the death-associated protein kinase protein kinase /pro·tein ki·nase/ (pro´ten ki´nas) an enzyme that catalyzes the phosphorylation of serine, threonine, or tyrosine groups in enzymes or other proteins, using ATP as a phosphate donor.  1 (DAPK1) gene on human chromosome 9 correlate strongly with risk for late-onset Alzheimer's disease. These research findings were presented today at the International Conference on Alzheimer's Disease 2006 in Madrid, Spain, and will appear in the August 2006 edition of Human Molecular Genetics, currently available online at http://hmg.oxfordjournals.org/papbyrecent.dtl.

In Celera's research studies, two single nucleotide polymorphisms (SNPs) were identified in DAPK1 that showed significant association with late-onset Alzheimer's disease in an analysis of up to six research sample sets with a total of 2,012 cases and 2,336 controls. In addition to the genetic finding, this research study also showed that the disease-associated SNPs directly or indirectly modulate the expression of the DAPK1 gene. This observation provides a potential biological explanation for the association of the DAPK1 variants with Alzheimer's disease.

"This research study provides valuable insights into the genetic contribution to Alzheimer's disease," said Michael Owen, Ph.D., Professor of Psychiatry at Cardiff University, United Kingdom, and a co-author on the paper. "The DAPK1 gene has been a target for drug discovery in other diseases, and a variety of drug compounds can now be tested for their effect on learning and memory in animal models of Alzheimer's disease."

DAPK1 is an enzyme involved in the programmed cell death pro·grammed cell death
n.
See apoptosis.



programmed cell death

proposed system of cell death, often including poly(ADP)-ribosylation, ensures that a cell will not survive if it is so badly damaged that its recovery would harm the
 cascade and evidence suggests that one of its functions is to control the death of nerve cells, and it is predominantly expressed in regions of the brain, such as the hippocampus hippocampus

fabulous marine creature; half fish, half horse. [Rom. Myth. and Art: Hall, 154]

See : Monsters
 and cortex, that are most severely affected by Alzheimer's disease. Increased DAPK1 activity or expression has been observed in nerve cell death, and nerves lacking DAPK1 are less susceptible to cell death in cell cultures and in certain animal models. Other evidence suggests that DAPK1 expression is indirectly modified by levels of the precursor form of the protein that forms the senile plaques Senile plaques
Abnormal structures, composed of parts of nerve cells surrounding protein deposits, found in the brains of people with Alzheimer's disease.

Mentioned in: Dementia
 that are characteristic for Alzheimer's disease. Another recent study reported that mice without DAPK1's kinase activity are more efficient learners and have better spatial memory than normal mice (Yukawa et al. 2006). DAPK1 is therefore believed to be an excellent biological candidate gene for contributing to the development of Alzheimer's disease.

These research findings are the latest in a series of research discoveries made by Celera and its collaborators regarding Alzheimer's. In the past year, Celera's scientists identified novel genetic variants in a homologue homologue /ho·mo·logue/ (hom´ah-log)
1. any homologous organ or part.

2. in chemistry, one of a series of compounds distinguished by addition of a CH2 group in successive members.
 of the RPS rps
abbr.
revolutions per second
3a gene (American Journal of Human Genetics The American Journal of Human Genetics is a leading journal in the field of human genetics. Since its inception in 1948 by the American Society for Human Genetics, the Journal has provided a record of research and review relating to heredity in humans and to the application , Grupe et al., 2006), the glyceraldehyde-3-phosphate dehydrogenase dehydrogenase /de·hy·dro·gen·ase/ (de-hi´dro-jen-as?) an enzyme that catalyzes the transfer of hydrogen or electrons from a donor, oxidizing it, to an acceptor, reducing it.

de·hy·dro·gen·ase
n.
 (GAPD GAPD Guard Capacity Adaptation Based on Prediction and Dropping ) gene (Proceedings of the National Academy of Sciences The Proceedings of the National Academy of Sciences of the United States of America, usually referred to as PNAS, is the official journal of the United States National Academy of Sciences. , Li et al., 2004) and also in the amyloid beta precursor protein binding family B, member 2 (APPB APPB Array Processor with Pipelined Bus
APPB Application Builder
2) gene (Human Mutation, Li et al, 2005). The previously reported associated markers and this marker in DAPK1 each consistently show an involvement in apoptotic cell apoptotic cell Cell biology A dense, eosinophilic, pyknotic cell surrounded by a thin clear space, often lying within epithelium, which is due to apoptosis  death shedding light on the fundamental underlying mechanism of disease, critical to new therapeutic options. Patent applications for these Celera findings are in process.

"These research findings also hold promise for enabling the development of diagnostic tests to identify people who may be at risk for Alzheimer's and would potentially benefit from treatment with DAPK1 inhibitors," said Thomas White, Ph.D., Chief Scientific Officer at Celera. "We intend to partner or license any potential therapeutic value that emerges from this research program."

Study Details

To identify genetic variants associated with Alzheimer's disease in the region on chromosome 9 that is thought to harbor a genetic risk for the disease, SNPs were scanned across the entire chromosome using DNA DNA: see nucleic acid.
DNA
 or deoxyribonucleic acid

One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes.
 samples collected from research subjects and similar non-demented individuals. The scan was carried out in a multi-stage fashion (including discovery and replication) and primarily targeted SNPs that may lead to changes in gene or protein function or activity. The DAPK1 SNP SNP Scottish National Party

Noun 1. SNP - (genetics) genetic variation in a DNA sequence that occurs when a single nucleotide in a genome is altered; SNPs are usually considered to be point mutations that have been evolutionarily
 survived replication in multiple data sets and was then further tested in three additional validation sets. When analyzing all sample sets combined, individuals with two copies of the risk gene variant were at 1.4-fold greater risk for the development of disease. To identify potential causative variants, additional dense genotyping in the DAPK1 region was then performed.

Following the genetic research study, a biological characterization of DAPK1 gene expression was carried out and it was found that DAPK1 gene expression shows differences between the copies on each of the two chromosomes. The DAPK1 copy-specific expression was then correlated to the genotypes of the Alzheimer's-associated SNPs.

The lead author of this paper was Yonghong Li, Ph.D., Staff Scientist, CNS See Continuous net settlement.

CNS

See continuous net settlement (CNS).
 Discovery Research at Celera. The work was conducted in collaboration with researchers at Washington University, St. Louis, Missouri, Cardiff University in Wales Wales, Welsh Cymru, western peninsula and political division (principality) of Great Britain (1991 pop. 2,798,200), 8,016 sq mi (20,761 sq km), west of England; politically united with England since 1536. The capital is Cardiff. , United Kingdom, the National Institute of Aging, Bethesda, Maryland, Cambridge University, United Kingdom, King's College London, United Kingdom, and the University of California, San Diego UCSD is consistently ranked among the top ten public universities for undergraduate education in the United States by U.S. News & World Report.[3] It is a Public Ivy. [1] For graduate studies, most of UCSD's Ph.D. , California.

About Alzheimer's disease

An estimated 4.5 million Americans suffer from Alzheimer's disease and that number is expected to grow to as many as 16 million by 2050 (Herbert et al., 2003).

Alzheimer's disease, the most common form of dementia among the elderly, is a complex neurodegenerative disorder neurodegenerative disorder Neurology A chronic progressive neuropathy characterized by selective and generally symmetrical loss of neurons in motor, sensory, or cognitive systems Types by area Cerebral cortex–Alzheimer's disease, Pick's disease, Lewy body  resulting from multiple genetic and nongenetic factors (Myers & Goate, 2001). The most common form occurs later in life and appears sporadically. However, several risk-factor genes have been implicated im·pli·cate  
tr.v. im·pli·cat·ed, im·pli·cat·ing, im·pli·cates
1. To involve or connect intimately or incriminatingly: evidence that implicates others in the plot.

2.
 as causes of the disease. For example, a large body of evidence supports a central role for (beta)-amyloid. A well established genetic risk factor previously identified for the late-onset disease is a gene that makes one form of a protein called apolipoprotein E (APOE APOE ε4 Molecular neurology The type 4 allele of the apolipoprotein E gene locus located on chromosome 19, which may↑ the risk of late-onset Alzheimer's disease, and has been associated with ↓ cerebral parietal metabolism; possession of an  4). Genetic modeling and whole genome linkage scans have implicated several genes in the genetics of sporadic Alzheimer's, but the precise genes which modulate the risk of Alzheimer's remain to be confirmed.

Advancing age is the most important known risk factor for Alzheimer's. The disease usually begins after age 60, and the number of people with the disease doubles every 5 years beyond age 65. About 5 percent of men and women ages 65 to 74 have Alzheimer's, and nearly half of those age 85 and older may have the disease. While younger people also get Alzheimer's, it is much less common.

National direct and indirect annual costs of caring for individuals with Alzheimer's are estimated to be at least $100 billion. It is estimated that Alzheimer's disease costs American business more than $61 billion a year, and of that figure, $24.6 billion covers Alzheimer health care and $36.5 billion covers costs related to caregivers of individuals with Alzheimer's, including lost productivity, absenteeism and worker replacement (Koppel, 2002).

About Celera Genomics and Applera Corporation

Applera Corporation consists of two operating groups. The Celera Genomics Group uses proprietary genomics and proteomics discovery platforms to develop molecular diagnostic products and to identify and validate novel drug targets. Celera maintains a strategic alliance in molecular diagnostics with Abbott. In addition, Celera is developing new molecular diagnostic and pharmacogenomic assays outside of its alliance with Abbott. Therapeutic antibodies against Celera-discovered drug targets are being advanced through strategic partnerships. The Applied Biosystems Group serves the life science industry and research community by developing and marketing instrument-based systems, consumables, software, and services. Customers use these tools to analyze nucleic acids (DNA and RNA RNA: see nucleic acid.
RNA
 in full ribonucleic acid

One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic
), small molecules, and proteins to make scientific discoveries and develop new pharmaceuticals. Applied Biosystems' products also serve the needs of some markets outside of life science research, which we refer to as "applied markets," such as the fields of: human identity testing (forensic and paternity testing); biosecurity, which refers to products needed in response to the threat of biological terrorism and other malicious, accidental, and natural biological dangers; and quality and safety testing, for example in food and the environment. Applied Biosystems is headquartered in Foster City, CA, and reported sales of nearly $1.8 billion during fiscal 2005. Information about Applera Corporation, including reports and other information filed by the company with the Securities and Exchange Commission, is available at http://www.applera.com, or by telephoning 800.762.6923. Information about Celera Genomics is available at http://www.celera.com.

Forward-Looking Statements

Certain statements in this press release are forward-looking. These may be identified by the use of forward-looking words or phrases such as "believe," "expect," "intend," "should," and "planned," among others. These forward-looking statements are based on Applera Corporation's current expectations. The Private Securities Litigation Reform Act The Private Securities Litigation Reform Act of 1995 (PSLRA) implemented several significant substantive changes affecting certain cases brought under the federal securities laws, including changes related to pleading, discovery, liability, class representation and awards fees and  of 1995 provides a "safe harbor" for such forward-looking statements. In order to comply with the terms of the safe harbor, Applera Corporation notes that a variety of factors could cause actual results and experience to differ materially from the anticipated results or other expectations expressed in such forward-looking statements. These factors include but are not limited to: (1) Celera's unproven ability to discover, develop, or commercialize proprietary diagnostic products; (2) the uncertainty that Celera's products will be accepted and adopted by the market, including the risk that these products will not be competitive with products offered by other companies, or that users will not be entitled to receive adequate reimbursement for these products from third party payors such as private insurance companies and government insurance plans; (3) reliance on existing and future collaborations with other companies, including its strategic alliance with Abbott Laboratories, which may not be successful; (4) uncertainty of the availability to Celera of intellectual property protection, limitations on its ability to protect trade secrets, the risk of infringement claims, and the possibility that it may need to license intellectual property from third parties to avoid or settle such claims; (5) legal, ethical, and social issues which could affect demand for Celera products; and (6) other factors that might be described from time to time in Applera Corporation's filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Applera does not undertake any duty to update this information, including any forward-looking statements, unless required by law.

Copyright(C) 2006. Applera Corporation. All rights reserved. Applied Biosystems and Celera are registered trademarks and Applera and Celera Genomics are trademarks of Applera Corporation or its subsidiaries in the U.S. and/or certain other countries.

References

Grupe A, Li Y, Rowland C, et al. "A scan of chromosome 10 identifies a novel locus showing strong association to Alzheimer's disease". American Journal of Human Genetics 2006; 78:78-88.

Hebert, LE; Scherr, PA; Bienias, JL; Bennett, DA; Evans, DA. "Alzheimer Disease in the U.S. Population: Prevalence Estimates Using the 2000 Census." Archives of Neurology The Archives of Neurology is a monthly professional medical journal published by the American Medical Association. Archives of Neurology publishes original, peer-reviewed scientific research of the nervous system as well as the various mechanisms of disease.  August 2003; 60 (8): 1119 - 1122.

Koppel, R. Alzheimer's Disease: The Costs to U.S. Businesses in 2002. Washington, D.C.: Alzheimer's Association; 2002.

Li Y, Nowotny P, Holmans et al. "Association of late-onset Alzheimer's disease with genetic variation in multiple members of the GAPD gene family". Proceedings of the National Academy of Sciences USA 2004; 101: 15688-15693.

Li Y, Hollingworth P, Moore et al. "Genetic association of the APP binding protein 2 gene (APBB APBB Amyloid Beta A4 Precursor Protein-Binding, Family B
APBB Advanced PROM Building Blocks
2) with late onset Alzheimer disease". Human Mutation 2005; 25: 270-277.

Myers, A. J. & Goate, A. M. (2001) Curr. Opin. Neurol. 14, 433-440.

Yukawa, K., Tanaka, T., Bai, T. et al. "Deletion of the kinase domain from death-associated protein kinase enhances spatial memory in mice". International Journal of Molecular Medicine. 2006: 17:869-873.
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