Alzheimer Related News Items

News as of 2/05/06

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Obesity Linked to AD Protein - As body fat increases, so do blood levels of an amyloid-beta 42 protein fragment linked to AD, a new study shows, which may begin to explain the recently reported association between obesity and AD. “We found that obesity by itself, even in otherwise healthy middle-aged people, is associated with elevated levels of the amyloid peptide that builds up and causes AD,” Dr. Sam Gandy, director of the Farber Institute for Neurosciences in Philadelphia and one of the study’s authors, told Reuters Health. “Amyloid is normally made all throughout the body at various lengths,” Gandy explained. “This particular form is believed to be the form that initiates build-up of amyloid plaques in the brain.” Gandy, Dr. Ralph Martins at Edith Cowan University in Joondalup, Western Australia and their colleagues investigated whether levels of the peptide, plasma amyloid-beta 42,were related to body mass index (BMI) or fat mass in 18 healthy adults. As BMI rose, so did amyloid-beta 42 blood levels. The same was true for fat mass. But there was no relationship between BMI or fat mass and another peptide, amyloid-beta 40, which is not associated with disease. Obesity-linked conditions like diabetes and heart disease may also increase AD risk, but when Gandy and his team adjusted the data for levels of insulin, cholesterol, and inflammation in an attempt to account for their influence, the fat-amyloid-beta 42 relationship remained. This suggests, Gandy said, that it’s the fat itself -- not the diseases that excess weight can cause -- that may be increasing levels of the dangerous protein. “The amyloid beta is very attracted to fat,” he noted. “It might make sense that having a lot of lipids around would increase your tendency to hang on to a lot of amyloid beta rather than metabolizing it.” The potentially harmful protein could be stored up in body fat the same way that fat-soluble drugs and hormones are, he added. The next step, Gandy said, will be to follow participants in the current study to see if any subjects develop AD and to investigate potential mechanisms for the fat-amyloid-beta-42 in the laboratory. By Anne Harding Reuters Health 1/10/06 Journal of Alzheimer’s Disease, Dec. 2005, Vol. 8, No. 3, 269-282

Two Pathways Found That Lead To AD - Mild cognitive impairment (MCI), a transitional stage between normal cognition and AD, exists in two different forms, according to a study published 1/17/06 by researchers from the University of Pittsburgh School of Medicine and the University of California, Los Angeles in the Archives of Neurology. Using a new imaging procedure that creates 3-D maps of the brain, researchers determined specific areas that had degenerated in people with MCI. Depending on the person’s symptoms, more tissue was lost in the hippocampus, a brain area critical for memory and one of the earliest to change in AD, indicating two different paths of progression to AD. The finding could lead to better diagnosis and treatment of patients with MCI, perhaps delaying or preventing the onset of dementia. MCI is categorized into two sub-types -- currently distinguished based solely on symptoms. Those with MCI, amnesic subtype (MCI-A) have memory impairments only, while those with MCI, multiple cognitive domain subtype (MCI-MCD) have other types of mild impairments, such as in judgment or language, but also have either mild or no memory loss. Both sub-types progress to AD at the same rate. Until now it was not known if the pathologies of the two types of MCI were different, or if MCI-MCD was just a more advanced form of MCI-A. Researchers found that the hippocampus of the patients with MCI-A was 14 percent smaller than that of the healthy subjects, nearly as great as the 23 percent shrinkage seen in AD. But, the hippocampus of those with MCI-MCD most resembled that of the controls, showing only 5 percent shrinkage. Using highly accurate Magnetic Resonance Imaging (MRI) data the researchers created 3-D mesh reconstructions of each participant’s hippocampus that allowed them to see where the hippocampus had deteriorated. This study is the first to use such modeling technology to visualize changes in the brains of people with MCI. Prior studies have only been able to measure the volume of the hippocampus and estimate atrophy through noticeable volume loss. “These vibrant images produced by 3-D modeling have proven what we suspected -- there are at least two transitional states that lead to AD,” said James T. Becker, Ph.D., a neuropsychologist and professor of psychiatry, neurology and psychology, at the University of Pittsburgh School of Medicine and lead author of the study. “Now we can investigate these pathways and develop treatments that, we hope, may slow or stop the progression of AD.” ScienceDaily.com 1/17/06 Archives of Neurology, 2006;63:97-101

Drugs

AD Drugs Offer Modest Improvements, Equal Effectiveness - The AD drugs Aricept, Razadyne and Exelon can lead to small improvements in mental functioning and the ability to carry out everyday activities in people with mild to moderate forms of the disease, according to a new review of recent studies. Although the three drugs work in slightly different ways, the few head-to-head studies of the drugs - - all funded by pharmaceutical companies - - found them equally effective, according to review author Jacqueline Birks of the University of Oxford. The review appears in the January issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic. Birks’ review included 13 high-quality studies involving 7,298 patients from North America, Europe and Australia. The studies compared the three drugs against placebo treatment, with 2,228 patients in the Aricept studies, 2,267 in the Razadyne studies and 2,803 in the Exelon studies. The effects of the drugs were not very large when measured across the 13 studies, Birks found. In one measure of how well the drugs worked, for instance, patients across the studies improved by an average of less than three points on a 70-point scale that tracks mental functioning. “There is nothing to suggest the effects are less for patients with severe dementia, although there is very little evidence for other than mild to moderate dementia,” she said. By Becky Ham, Science Writer Health Behavior News Service 1/24/06 The Cochrane Database of Systematic Reviews 2006, Issue 1, Art. No.: CD005593

British Watchdog Backs Limited AD Drug Use - Cost-effectiveness watchdog NICE said 1/23/06 that AD drugs which can help, but not cure, some patients should be used in a minority of people with the degenerative brain disease. The decision is a partial climbdown by the National Institute for Health and Clinical Excellence (NICE), which last year suggested so-called anti-cholinesterase drugs were not worth the money for any patients. The new guidance, which is subject to further consultation but is likely to become final by July, means three drugs will in future be prescribed on the state health service -- but only for those with AD of moderate severity. Such cases, accounting for approximately 40 percent of all patients, includes people with a mini mental state examination (MMSE) score of between 10 and 20 points. Newly diagnosed AD patients with mild disease will not get access to the medicines. Andrew Dillon, chief executive of NICE, said the plan for restricted use had been drawn up after analysis of additional clinical information provided by manufacturers. “By going the extra mile and asking the drug companies to delve deeper into their clinical trial data, we have been able to identify the right way to use these medicines,” he said. “People with AD will now receive these drugs when they can help them most.” But physicians, patient groups and drug companies criticised the decision as short sighted and said it was worrying that patients with early disease will be excluded. “In every other branch of medicine, the emphasis is on finding and treating early signs before the illness progresses. Yet NICE proposes a different medical approach with dementia. It makes no clinical sense,” said Dr Paul Hooper, the managing director of Eisai Co Ltd. Pfizer Inc and Eisai Co Ltd’s Aricept is the market leader among anti-cholinesterase treatments. Reuters 1/23/06 By Ben Hirschler, European Pharmaceuticals Correspondent

Memantine Appears Effective and Safe in Moderate to Severe AD - Memantine, a drug approved for the treatment of AD, appears safe and effective in patients with moderate to severe cases of AD. Various chemical and other processes in the brain may contribute to the development of AD. Memantine appears to act on one of those pathways, which involves the neurotransmitter glutamate, the authors report. The drug was approved in the United States in 2003 and also is available in the European Union and Australia. Barry Reisberg, M.D., from the New York University School of Medicine, and colleagues conducted a 24-week open-label extension trial. In this type of trial, participants who had previously been part of a double-blind study--where some were taking an active drug and some were taking a placebo--were all given the same amount of the active drug. For this study, 175 patients with moderate to severe AD who completed the previous 28-week study received 20 mg of memantine daily for an additional 24 weeks. The authors report that during the study, cognitive tests, reports from caregivers and observations by clinicians all indicated that memantine was beneficial to AD patients. “The benefits of memantine seen in the double-blind phase were again observed when patients treated with placebo were switched to memantine treatment in the open extension,” they write. “For the patients who were randomized to memantine treatment during the double-blind phase, these clinically relevant benefits also appeared to be maintained in sum.” The completion rate for the extension phase was high (78 percent) and the adverse event profile for memantine was similar to that observed in the double-blind study. PR 1/9/06 Archives of Neurology, 2006;63:49-54  

Axonyx Completes First Phase I Trial with Posiphen for AD Progression - Axonyx Inc. announced 1/24/06 completion of the ascending single dose Phase I trial with Posiphen, in clinical development for the treatment of AD progression. This double-blind, placebo controlled study of Posiphen in healthy men and women sought to establish well tolerated doses. Posiphen appears to be well tolerated at single doses up to and including 80mg. Blood levels of Posiphen associated with this study were higher than those associated with beneficial effects on beta- amyloid metabolism in animal models. The build-up of beta-amyloid (A beta) is generally believed to be causative of the dementia of AD. No serious adverse events were reported at any dose level. Current treatment of AD focuses primarily on acetylcholinesterase inhibition. Posiphen appears to modify the metabolism of beta-amyloid precursor protein (beta-APP). A major pathological hallmark of AD is the appearance of senile plaques that are primarily composed of aggregated forms of beta-amyloid (A beta) derived from beta-APP. Soluble forms of A beta have been shown to cause significant toxicity in vitro and in vivo and hence represent a target for drug development in AD treatment. The Company anticipates initiating a Phase I ascending multiple dose study in the near future. Gen Eng News 1/24/06

Testing

Sensor May Detect AD Markers - An Ocean Optics UV/VIS spectrometer is part of a nanosensor used by researchers at Northwestern University in Illinois to examine the behavior of molecules that may have a role in AD. The device has provided new information relevant to the understanding and possible diagnosis of the disease. At present, there is no definite clinical diagnosis for AD, but ADDLs (amyloid-derived diffusible ligands) -- miniscule toxic proteins suspected of triggering the disease -- are present at levels up to 70 times greater in autopsied brain samples from humans with AD than in humans without it. A sensitive way to detect ADDLs in body fluid could, therefore, be a basis for the laboratory diagnosis of AD, Ocean Optics said. The nanosensor developed for ADDLs is based on tiny, triangular silver particles that absorb and scatter light. The extinction spectrum (the sum of adsorbed and scattered light) of the nanoparticles varies as the environment surrounding the nanoparticles changes. To control this change, the nanoparticles’ surfaces are modified with a layer of ADDL-specific antibodies. These antibodies bind specifically to any ADDL molecules found in the samples studied. When this happens, the spectral properties of the silver nanoparticles shift slightly. Using this technique, the researchers were able to detect ADDL levels that were elevated in diseased patient samples in comparison to control patient samples. The researchers detected these color shifts using an Ocean Optics S2000 fiber optically coupled spectrometer. “The research has shown the potential of nanoscale optical biosensors is far-reaching and will aid in the development of other successful nanotechnology-based devices,” Ocean Optics said in a statement. Photonics.com 2/2/06

Prevention

A Dose of Exercise to Thwart Dementia - Three or more days of exercise a week could stave off dementia in older people, according to a new study led by Seattle researchers. The study followed 1,740 people age 65 and older for an average of six years. None showed signs of AD or other forms of dementia when the study began. Those who reported exercising three or more days a week were 30 percent less likely to develop dementia than others who exercised less or not at all. In addition, three days of exercise appeared to be most helpful for the least fit of the study participants. Still, because the study is observational -- that is, researchers asked people about their exercise routines, rather than assigning a particular type of activity for a set amount of time to different groups -- it doesn’t specify how much and what types of exercise make the most difference. “It’s not really definitive evidence. But on the other hand, what do we do while we wait for definitive evidence? We have lots of reasons to exercise, so perhaps this is another reason,” said Dallas Anderson at the National Institute of Aging, which funded the study. Exercise, intellectual engagement, a healthy diet and social interaction appear to help delay dementia, although it’s not clear which of these factors is most successful or why. One theory about the connection between exercise and dementia is that physical activity increases blood and oxygen flow, making the brain more equipped to withstand the stress of aging, said Dr. Eric Larson, lead author of the study and director of the Center for Health Studies at Group Health Cooperative. By Julie Davidow Seattle Post-intelligencer Reporter 1/17/06 Annals of Internal Medicine 17 Jan 2006:144(2) 73-81 free copy at http://www.annals.org/cgi/content/full/144/2/73 The lead author Eric Larson was interviewed on Science Friday on Jan 27, 2006. The 12 min, 32 sec audio on dementia is at

http://www.sciencefriday.com/pages/2006/Jan/hour1_012706.html

To Sharpen the Brain, First Hone the Body - Over the last decade, neuroscientists have been churning out an abundance of data pointing to changes in the brain following physical activity. Some researchers have even suggested that the type of exercise matters — as does the age at which it begins. “I would absolutely recommend people exercise for the mental benefits — especially the elderly,” says Henriette Van Praag, a staff scientist at the Salk Institute for Biological Studies in La Jolla. “People don’t care about whether they’re a size 4 or a size 6 as they get older. But they do care where their car keys are and whether they’ll have the ability to play their card games and enjoy life.” Movement appears to enhance memory, learning, attention, decision-making and multi-tasking, among other mental functions. It also may slow or even reverse age-related decline. The proof comes in two forms. The first is research showing that people who exercise score better on mental tests than those who don’t. Most of this research has been on older people. The second is research showing that exercise prompts structural changes in the brains of mice, spurring the growth of new nerve cells and connections between those cells. While admittedly a far cry from human studies, the finding that new neurons can be formed later in life — called neurogenesis — is a revelation. Scientists had long assumed that we have at birth all the nerve cells we will ever have, losing them as we age. “Neurogenesis is probably a very important contributor to the effects of exercise on learning and memory,” Van Praag says. A study published in September in the Journal of Neuroscience by Van Praag and the Salk researchers showed that the new neurons in older mice who began exercising were twice those of young, sedentary mice. The older, exercising mice were also better able to learn new tasks. “The sedentary mice barely learned the task at all,” says Van Praag. “The aged runners were almost as good, if not better, than the young sedentary mice. It was almost a reversal of mental decline.” Exercise seems to enhance brain performance in three basic ways. One, it increases the flow of oxygen to the brain and may help build tiny blood vessels that pave the way for the growth of new cells. Two, it boosts substances called growth factors, including one called brain-derived neurotrophic factor that is critical to the survival of new nerve cells. Finally, physical activity increases chemicals in the brain called neurotransmitters, such as dopamine, serotonin and norepinephrine, which play a role in cognition. By Shari Roan, LA Times Staff Writer 1/9/06 Journal of Neuroscience, Sept. 21, 2005, 25(38):8680-8685

Black Currants May Help Thwart AD - Compounds in black currants may help protect against AD, according to a study in Chemistry & Industry magazine. Researchers found that these compounds -- anthocyanins and polyphenolics -- had a strong protective effect in cultured neuronal cells. Darker black currants contain more anthocyanins and are likely to be more potent. “These compounds also work in hippocampal cells taken straight from the brain,” researcher James Joseph of Tufts University said in a prepared statement. He said these protective effects will likely be reproduced in the human body and that these compounds may prevent or significantly delay the onset of AD. While previous research found that compounds in black currants acted as antioxidants, this is the first study to demonstrate that they may help protect brain cells. Exactly how they do this remains unclear, the study said. “We have evidence that the compounds protect against AD by influencing the early gene expression in learning and memory, which influences cell signaling pathways that help neuronal cells communicate with each other,” Joseph said. HealthDay News 1/23/06 Chemistry & Industry 23 Jan. 2006, Issue 2, pg. 6

Thinking May Harm People with Chronic Brain Diseases -The process of thinking may actually be harmful to people with chronic brain diseases such as HIV dementia and AD. Scientists at the University of Rochester Medical Center have discovered a rather alarming mechanism: The inflammation triggered by these conditions turns normal nerve impulses -- neurons talking to one another -- into a toxic language that can damage cells outright. Dr. Harris A. Gelbard, a professor of neurology and principal investigator of the study published recently in the Journal of Clinical Investigation, has been researching the brain circuitry that goes awry in these mind-robbing conditions. Gelbard and Matt Bellizzi witnessed under a microscope disturbing behavior in dendrites, the branchlike part of the neuron that conducts impulses from the body of the cell to another cell. Dendrites have spines sprouting out like twigs, and at the end of the curved branch is a synapse, a chemical handshake with the neighboring cell. Cells need the synapse to communicate. Gelbard and Bellizzi saw that the dendrites growing in the damaged brain were beading -- creating a foxhole and disappearing. The synapse couldn’t function properly. Then -- surprise -- the beading stopped and the dendrite’s disappearing act was over. The synapse was also restored. Gelbard and his colleagues realized that the beading -- the disappearing act -- was associated with functional deficits in the cell. When inflammation wasn’t present, normal cell-to-cell communication flowed. This dendritic beading has also been observed in the brains of animals with AD. AIDS brains had the same beading. When nerves tried to communicate during a learning experience, the inflammation triggered this beading and prevented information from getting from one cell to the next. Abnormal amounts of calcium were also produced. Once Gelbard realized that inflammation was at the heart of this process, he began testing drugs to quiet this abnormal immune response. “We got the idea to use a drug that buffers calcium and reduces inflammation,” said Gelbard. And it worked. Pretreating with a medicine normally used in emergency rooms to treat severe hypertension, Gelbard found that it prevented beading. “It saved the synapse,” he said. “It has to get to the right place and in the right dose, but you can do almost anything to neurons and they won’t die.” He believes that this approach, conditioning neurons to withstand stress, could be used in early stages of dementia to strengthen vulnerable cells. The National Institute of Mental Health is testing a variety of compounds to treat AIDS dementia. One class of drugs being studied is the anti-epileptic medicines that appear to have anti-inflammatory properties. Clinical trials are under way. Gelbard’s work was funded by the same agency. By Jamie Talan Staff Writer Newsday 2/2/06 Journal of Clinical Investigation, 115:3185-3192 (2005)

Other Items

Receptor Critical in Neurodegeneration Reduces AD Plaque - Increasing the level of a protein that plays a key role in traumatic spinal cord injuries and multiple sclerosis reduces the concentration of disease-causing plaque in AD Yale School of Medicine researchers report. “Our new findings indicate that pharmacological methods to increase the protein, NogoReceptor, may be a way to treat the deficits associated with AD,” said Stephen Strittmatter, M.D., senior author of the study and co-director of the new program in Cellular Neuroscience, Neurodegeneration and Repair at Yale. It is well known that the clinical dementia of AD is associated with specific pathological changes in the brain. One such change is deposits of the peptide beta-amyloid in brain plaques, a hallmark of the disease. Nerve fibers also play a crucial role in the neurodegenerative process of AD. “We asked whether those mechanisms that regulate nerve fiber growth might lessen the AD process,” said Strittmatter, professor in the Departments of Neurology and Neurobiology. In brain sections from AD patients, the protein NogoReceptor is distributed in an unusual pattern in conjunction with beta-amyloid peptide, which is the primary component of plaque that forms in the brains of patients with AD, he said. “Using genetic mouse models, we show that the NogoReceptor and beta-amyloid bind to one another,” Strittmatter said. “Therefore, we investigated whether the NogoReceptor might alter the AD process.” “Using an AD model in mice, we demonstrated that decreasing the level of NogoReceptor causes more of the AD beta-amyloid to build up in the brain,” he said. “Conversely, higher levels of NogoReceptor reduced the concentration of the disease- causing beta-amyloid in the brain.” Strittmatter’s laboratory previously determined that a molecular pathway involving the NogoReceptor protein played a crucial role in determining whether nerve fibers grow or remain stationary in the adult brain. The protein inhibits the regeneration of axonal nerve fibers in injured spinal cords and in neurodegenerative diseases such as multiple sclerosis. PR 2/2/06 Journal of Neuroscience, Feb. 1, 2006, 26(5):1386-1395

Compound Stops AD Brain Cell Loss - Northwestern University scientists say they have developed a novel orally administered compound to help AD patients. The compound reportedly halts brain cell inflammation and neuron loss associated with AD. The researchers note the compound is also rapidly absorbed by the brain and is non-toxic -- important considerations for a central nervous system drug that might need to be taken for extended periods. The compound, called MW01-5-188WH, selectively inhibits production of pro-inflammatory proteins called cytokines by glia. Those are cells of the central nervous system that normally help the body mount a response, but are overactivated in certain neurodegenerative diseases -- such as AD and Parkinson’s disease, stroke and traumatic brain injury. The compound was designed and synthesized in the laboratory of D. Martin Watterson, a professor of cell and molecular biology at Northwestern University’s Feinberg School of Medicine. UPI 1/19/06 Journal of Neuroscience, Jan. 11, 2006, 26(2):662-670

Study Links AD to Abnormal Cell Division - A new study in mice suggests that AD may be triggered when adult neurons try to divide. The finding helps researchers understand what goes wrong in the disease and may lead to new ways of treating it. For unknown reasons, nerve cells (neurons) affected by AD and many other neurodegenerative diseases often start to divide before they die. The new study shows that, in animal models of AD, this abnormal cell division starts long before amyloid plaques or other markers of the disease appear. Cell division occurs through a process called the cell cycle. “If you could stop cell cycling, you might be able to stop neurons from dying prematurely. This could be a fresh approach to therapy for AD and other diseases, including stroke, amyotrophic lateral sclerosis [also known as Lou Gehrig’s disease], and HIV dementia,” says Karl Herrup, Ph.D., of Case Western Reserve University in Cleveland, who led the study. The researchers compared the brains of three different mouse models of AD to brains from normal mice, looking specifically for markers of cell cycling. They found that, in the AD mouse models, cell cycle-related proteins appeared in neurons 6 months before the first amyloid plaques or disease-related immune reactions developed in the brain. Many of the neurons also had increased numbers of chromosomes, which is typical of cells that have begun to divide. These changes were not seen in normal mice. The regions of the brain most affected by the neuronal cell cycling were the cortex and the hippo-campus – the same regions most affected in AD. The cortex is important for thought and reasoning, while the hippocampus plays a key role in learning and memory. Some parts of the brainstem also showed evidence of cell cycling. While the cell cycling appeared to be necessary for neurons to die, it was not an immediate cause of cell death in the mouse models of AD. Instead, the affected neurons appeared to live for many months in a near-functional state, with the mice showing only mild behavioral changes during that time. This suggests that another type of cellular problem, still unidentified, must damage the neurons in order for them to die. The findings shed new light on the theory that the accumulation of amyloid beta in the brain causes the neuron death in AD. Because the abnormal cell cycling begins months before the formation of amyloid plaques, it is unlikely that the plaques themselves trigger the disease process. However, tiny clumps made up of several amyloid beta molecules (called micro- molecular aggregates) form before the plaques and may trigger the disease. Since the three mouse models tested in this study all had mutations in the gene that codes for amyloid precursor protein, the similarity between affected brain regions in these mice and in people with AD also supports the amyloid hypothesis. While previous studies have linked AD to abnormal cell cycling, this is the first study to examine the link using standard mouse models of AD. The results indicate that the mice, which do not develop neurofibrillary tangles or the severe behavioral symptoms of AD, are accurate models of the early cellular processes that lead to the disease. “The cell cycle markers mimic the human situation rather well,” says Dr. Herrup. “This opens a range of new experimental possibilities using the cell cycle events as indicators of neuronal distress.” PR 1/17/06 Journal of Neuroscience, Jan. 18, 2006, 26(3):775-784

Epsilon4 Allele Carriers Show Altered Brain Activity Before Onset of AD Symptoms - Healthy individuals who are at risk of AD show reduced activity in the hippocampal region of the brain when performing tasks related to forming new memories. In a study published 1/12/06 in the open access journal BMC Medicine, individuals carrying the apolipoprotein E (APOE) epsilon4 allele, which has previously been associated with high risk of developing AD, showed altered brain activity compared to APOE epsilon3 homozygotes. According to the authors of the study, this supports the idea that certain regions of the brain exhibit functional decline associated with the APOE epsilon4 allele, and this decline begins before the onset of AD symptoms. Mehul Trivedi and colleagues from the University of Wisconsin Medical School and the William S. Middleton Memorial VA Hospital, Madison, United States, used functional magnetic resonance imaging (fMRI) scanning to analyse the brain activity patterns of 40 apparently healthy middle-aged individuals with a family history of AD, comparing epsilon3/4 heterozygotes with epsilon3/3 homozygotes. In this test the participants were asked to distinguish between images that they were being shown for the first time and images that they had already memorized previously in a pre-scan training session. During the task, the epsilon3/4 heterozygotes showed reduced activation in the medial temporal lobe (MTL) of the brain, including the right hippocampus, compared to the epsilon3/3 homozygotes. There were no differences between the two groups in age, education, performance during the task or neuropsychological assessment of memory; therefore the altered brain activation seen could not have been caused by impaired cognitive function. According to the authors, “if compromised MTL function continues to be observed in healthy epsilon4 carriers, this group of subjects may represent a good study population for novel treatments designed to delay the onset or to prevent the development of AD.” PR 1/12/06 BMC Medicine 2006, 4:1 (13 Jan 06)

Key Heart and AD Protein (APOE4) Imaged for First Time in Native State - Researchers for the first time have created a three-dimensional image of apolipoprotein E, a protein long associated with cardiovascular disease and more recently with AD, as it appears when it is bound to fat-like substances known as lipids. Using the technique known as x-ray crystal-lography, scientists at the Gladstone Institute of Cardiovascular Disease (GICD) have created the highest-resolution x-ray structure of a lipoprotein particle to date. The work focuses apoE4, one of three specific forms of apolipoprotein E, commonly known as apoE. The breakthrough has already answered long-standing questions about the configuration of apoE4 in its active, or native, state. A complete understanding of the protein’s functioning will be a key factor for development of future therapeutic interventions, according to the researchers. “This is the first successful use of x-ray crystallography to reveal the structure of a protein bound to lipids,” explains senior author Karl Weisgraber, PhD, a senior investigator at both GICD and the Gladstone Institute of Neurological Disease (GIND). “It’s crucial to understand this molecule, since it plays such a pivotal role in both cardiovascular and neurological disease. Lipid-bound proteins change their shape once they’ve bound to a lipid and have begun their key functions. Next to one’s age, the greatest known risk factor for AD is the gene for apoE4. ApoE4 is associated with 40-60 percent of cases of sporadic and familial AD. Everyone inherits two copies, or alleles, of every gene, one from each parent, Weisgraber explains. As the number of apoE4 alleles increases from 0 to 2, the risk of AD increases from 20 to 90 percent, and the typical age of onset decreases from 84 years to 68 years. The presence of one apoE4 allele results in an estimated 45 percent chance of developing AD by 85 years of age. With two apoE4 alleles, the risk increases to 50–90 percent. “Insights into the basic biology of apoE--and particularly apoE4--gained by Gladstone scientists have been invaluable in the study of AD,” says lead author Clare Peters-Libeu, a GICD and GIND research scientist. “Gaining a complete, three-dimension-al understanding of its configuration in its native, lipid-bound state will inevitably lead to even more insights into its role in cardiovascular and neurological disease in the years to come.” PR 1/12/06 Journal of Biological Chemistry, Vol. 281, Issue 2, 1073-1079, Jan. 13, 2006

New Medical Search Engine - The core mission of a new web site Healthline.com ( http://www.healthline.com ), which is owned by Healthline Networks, is to act as a medical search engine, finding articles on ailments and remedies from some 66,000 Web sites it has identified as providing medical content. In doing so, Healthline says it offers consumers a broader choice of information than WebMD, which is by far the most popular single medical resource online, and a more refined choice than general search engines like Google. By Bob Tedeschi NY Times 1/23/06

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