New Genetic Risk Factors for Late Onset Alzheimer’s Disease

In a study published February 22nd, 2007 in the journal Human Molecular Genetics, several new genes associated with late onset Alzheimer’s disease (LOAD) have been identified.  LOAD is the most common form of Alzheimer’s disease (AD) and strikes more then 3 million Americans. Unlike early onset AD, development of late onset AD is not caused by mutations in genes, but instead is influenced by genetic risk factors. The most well studied risk factor to date is possession of the epsilon 4 variant of the apolipoprotein E gene (ApoE). ApoE is a gene involved in lipid metabolism.  In this new report, scientists at Celera Diagnostics compared 17,343 genetic markers in 1808 LOAD cases with 2062 normal control subjects to identify new genes associated with LOAD. Several new candidate genes were identified in this way. One gene PCK1, encodes phosphoenolpyruvate carboxykinase 1. PCK1 is the main control point for the regulation of glucose production.  The other gene, GALP, encodes galanin-like peptide precursor. GALP is responsive to insulin and plays a role in regulating feeding behavior. This study supports the role of metabolism, and in particular glucose and insulin, in LOAD and fits well with Accera’s research efforts.

Reducing Insulin Signaling Protects Against Alzheimer’s Disease in a Nematode Model.

In a study published in August, 2006 in the journal Science, researchers at The Scripps Research Institute and the Salk Institute for Biological Studies have found that the reducing insulin-like signaling in a model of Alzheimer’s disease (AD) protects the animals from toxic properties of the Abeta peptide. The Abeta peptide accumulates in AD and is thought by many to be the causative agent of the disease.  The scientists used a worm (known as C. elegans) model of AD. C. elegans is a soil dwelling roundworm about 1 mm in length. The worms used in the study were engineered by Dr. Christopher Link at University of Colorado at Boulder to express large amounts of the Abeta peptide in muscle cells. Animals expressing Abeta progressively become paralyzed due to the toxic effects of the peptide. The researchers at Scripps and Salk Institutes examined the role of reducing insulin-like signaling in this model. Reducing insulin-like signaling in worms is well known to extend life span presumably by slowing the aging process. In the current study reducing insulin-like signaling also delayed the paralyzing effects of the Abeta in the animals. The protective effects of reduced insulin signaling were traced to increased activity of a protein called DAF-16. DAF-16 also mediates long life and stress resistance phenotypes in C. elegans.  This study further supports the role of insulin-like signaling as a modifying agent in AD and strongly supports the fundamental foundation of Accera, Inc. research efforts.

Hypometabolism in the Hippocampus Predicts Progression to Alzheimer's Disease

In a study published in the June 14th, 2005 issue of the journal Neurology, researchers at the New York University School of Medicine have found that early changes in hippocampal metabolism may predict who will get Alzheimer's disease (AD) nine years before symptoms appear. The hippocampus is a region of the brain that plays a key role in memory formation and is one of the major areas damaged in AD. The researchers tracked 53 healthy people for up to 24 years. During this time the subjects underwent conventional brain scans to measure glucose use in regions of the brain. Of these subjects six so far have developed Alzheimer's and 19 developed an Alzheimer's precursor called “mild cognitive impairment,” or MCI. The subjects who developed AD and MCI showed less glucose metabolism in the hippocampus up to 9 years before clinical symptoms were evident. Those subjects with normal hippocampal metabolism did not typically progress to AD or MCI. The researchers found that the lower energy usage in the hippocampus correctly identified who would get Alzheimer's or a related memory impairment 85 percent of the time. Identifying and correcting such metabolic defects offers a promising area of treatment for AD, and is the mission of Accera, Inc.

Hypometabolism Identified as an Early Marker for Alzheimer's Disease

Research at Banner Good Samaritan Medical Center in Phoenix, Arizona has demonstrated that conventional PET (Positron Emission Tomography) scans may be used as an “endophenotype” for Alzheimer's disease (AD). Normally, diagnosis of probable AD is based on neuropyschometric tests which are difficult to administer, yield variable results, and lack accuracy. The researchers at Banner health had previously shown that AD subjects exhibit a specific pattern of glucose hypometabolism in the brain that can be detected with a PET scan. In this study, the researchers measured cerebral glucose use in 160 cognitively normal elderly subjects (mean age 56 yrs) some of which carried the known genetic risk factor for late onset AD. Individuals who carry the epsilon 4 (E4) variant of a protein called apolipoprotein E are at increased risk for developing AD. The genetic risk behaves in a dominant dose dependent manner, such that carrying one allele increases the risk of AD, and carrying two alleles increases the risk even further. The authors of this study report that carriers of E4 also demonstrate a dominant dose dependent reduction in regional brain glucose use well before clinical signs of impairment can be detected with conventional testing. The researchers conclude that it may be possible to use metabolic measurements as quantifiable, accurate assays for both diagnosis and treatment of AD. The study was published in the June 7, 2005 issue of Proceedings of the National Academy of Science, USA. Accera, Inc. technology precisely targets these metabolic defects.

Axonal “Traffic Jams” May Lead to Alzheimer's Disease

Research by the University of California, San Diego (UCSD) School of Medicine published in the February 25, 2005 issue of the journal Science has suggested that disturbances in axonal trafficking are an early and possibly primary event in the development of Alzheimer's disease. The researchers found that abnormal amounts of vesicles and organelles were accumulating in axons of both mouse models of Alzheimer's disease and human patients suffering from the disease. These “traffic jams” preceded plaque formation and large scale amyloid beta peptide deposition. Thus, the failure of axonal transport may represent the primary event leading to cell death and formation of neuritic plaques. This fundamental discovery calls into question much of the current research in Alzheimer's disease, which seeks to rid the brain of amyloid. Such treatments may be closing the barn door after the horse has left.

Public Broadcasting System (PBS) - All Things Considered, National Public Radio, April 13, 2007 - Q&A: Alzheimer's Disease, Progress and Prospects.  An interview with Marilyn Albert, Professor of Neurology at Johns Hopkins University.

Public Broadcasting System (PBS) - "The Forgetting"

Scientists Probe Roles of Mitochondria in Neurological Disease and Injury Friedrich JAMA.2004; 291: 679-681 Article and video. A subscription or purchase may be required.

UCSD School of Medicine is Coordinating Center for National Alzheimer's Neuroimaging Initiative. Press Release. October 13, 2004.

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