01 Alzheimer Related News Items

News as of 3/5/06

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Top Items

Genes Play Major Role in AD Risk: Study - Genes may play a much bigger role in AD than previously thought and AD may have a genetic cause in up to 80 percent of cases, a new study involving twins suggests. “Our finding confirms the higher estimates that have been suggested previously,” said lead researcher Margaret Gatz, a professor of psychology at the University of Southern California, in Los Angeles. The study, which involves data on nearly 12,000 elderly participants in the Swedish Twin Registry, is 10 times larger than any previously done, Gatz said. “This doesn’t mean that environment is not important,” Gatz stressed. “Environment may be relevant not only for whether, but also for when one gets the disease. Also, you can’t go from these results to any one individual.” The researchers identified 392 pairs of twins where one or both had AD from the Swedish Twin Registry. All were aged 65 or over. The researchers looked at how common it was for identical twins to both have AD, or for only one to be affected.  They also looked at the same patterns in non-identical twins. It was more common for identical twins to both have AD compared to non-identical, and a statistical analysis of risk rates in the groups gave the researchers their estimate of how significant genetic factors are. The researchers estimated heritability - what proportion of risk for a disease across a population is genetic - for AD to be between 58% and 79%. HealthDay News 2/7/06 Archives of General Psychiatry, 2006;63:168-174  

AD Neuroimaging Initiative - This study will test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessment can be combined to measure the progression of mild cognitive impairment (MCI) and early AD. The information obtained by studying changes in the brain images of MCI and AD patients and healthy individuals, as well as other assessment tools, will be used to determine the best methods for measuring treatment effects in patients with MCI and AD. Approximately 800 participants, ranging in age from 55 to 90, will be recruited for the study: 400 patients with MCI, 200 with early AD, and 200 normal controls. Patients with MCI and normal controls will be followed for 3 years, and those with AD will be followed for 2 years. At 6-month intervals all participants will be seen in person or contacted by telephone. All participants will undergo repeated scanning and blood and urine biomarkers will be collected at the time of each scan. All patients will be asked if they are willing to undergo lumbar puncture at baseline and year one, with the goal of a minimum of 20% and as many as 50% of each group providing CSF samples for analysis and storage for future analyses. For more details see http://www.alzheimers.org/clinicaltrials/fullrec.asp?PrimaryKey=208  . One of the sites is Johns Hopkins University in Baltimore MD.

Drugs

Drug AF267B Blocks AD Course - A drug that appears to block the progression of AD has been identified by scientists at the University of California, Irvine. In tests on mice, the drug, AF267B, reversed the symptoms of memory loss and problems with learning associated with AD. Further analysis showed it also reduced levels of protein clumps and tangles often found in AD patients. The drug was developed to activate receptors for a brain chemical called acetyl-choline. These receptors are abundant in two areas of the brain - the cortex and hippocampus. Both are known to be particularly vulnerable to the build-up of the protein plaques and tangles that are so often found in the brains of AD patients, and which are thought to destroy brain cells. The researchers gave AF267B to mice engineered to show classic signs of AD. They found animals treated with the drug performed better at learning and memory tasks than untreated animals. The drug also cut levels of both protein plaques - found outside brain cells - and tangles - found inside the cells - in the cortex and hippocampus. The researchers also showed that AF267B appears to mimic the action of acetylcholine, binding to its receptors and boosting levels of enzymes involved in breaking down the key protein that forms clumps and tangles in brain cells. Lead researcher Professor Frank LaFerla said: “AF267B could be a tremendous step forward in the treatment of AD. Not only does it appear to work on the pathology of AD and ease its symptoms, it crosses the blood-brain barrier, which means it does not have to be directly administered to the brain, a significant advantage for a pharmaceutical product. Although we cannot determine what the effects of AF267B will be in humans until clinical trials are complete, we are very excited by the results our study has yielded.” BBC News 3/2/06 Neuron, Vol 49, 671-682, 02 March 2006

Samaritan Aims to Compete in AD Drug Market - Samaritan Pharmaceuticals Inc. said 2/27/06 it has licensed in a Spirostenol compound SP-233. It also noted that Lead Discovery, a scientific community update service, has recognized a peer-reviewed Neuroscience article relating to the drug as being of especial interest to the drug development sector. The article presents SP-233 as an example of a drug that was developed based on the bioactive steroids found in brain. Georgetown University has exclusively licensed the spirostenol derivative SP-233 to Samaritan Pharmaceuticals. Samaritan expects SP233 to be its first AD application to the FDA, Investigational New Drug (IND), and expects to file by mid-year. Genetic Engineering News 2/21/06 Neuroscience, vol 138, Issue 3, 2006 pg 749-756. The abstract is at http://dx.doi.org/doi:10.1016/j.neuroscience.2005.05.063

Genes & Genetic Issues

Researchers Discover a Natural Defense Mechanism for AD - A team from the Faculty of Medicine at Université Laval has discovered a natural defense mechanism that the body deploys to combat nerve cell degeneration observed in people with AD. AD is characterized by the accumulation of amyloid proteins in the brain. These proteins form plaques around which microglia, the central nervous system’s immune cells, aggregate. These microglia appear to be incapable of eliminating the plaques, and this has led some researchers to postulate that microglial action produces an inflammation causing neuronal death. The fact that AD patients are prescribed anti-inflammatory drugs results from this concept of the disease. For Serge Rivest and his team, microglia are not part of the problem, but of its solution. These investigators have observed that, although the brain’s resident microglia do appear to be poorly equipped for combating amyloid plaques, an entirely different case prevails for another type of microglia: those derived from bone marrow stem cells. Using tests conducted with transgenic mouse models of AD, the investigators have demonstrated that bone marrow-derived microglia infiltrate amyloid plaques and succeed in destroying them most efficiently. These newly- recruited immune cells are specifically attracted by the amyloid proteins that are the most toxic to nerve cells. According to Dr. Rivest, anti-inflammatory drugs should not be administered in cases of AD, as they interfere with this natural defense mechanism. On the contrary, he adds, a way must be found to stimulate the recruitment of a greater number of bone marrow-derived microglia. “Stem cells should be harvested from the patients themselves, thus limiting the risks of both rejection and adverse effects,” says Dr. Rivest. “While this cellular therapy will not prevent AD, by curbing plaque development, we believe that it will help patients prolong their autonomy and cognitive capacity. We believe that this is a new and powerful weapon in the fight to conquer AD.” Newswire Canada 2/16/06 Neuron,Vol 49, 489-502, 16 Feb 2006

AD and Parkinson’s Disease Treatment May Involve Gene Therapy - UCLA Researchers Found KCNC3 Gene Mutation - Researchers led by Dr Stefan Pulst at the Cedars-Sinai Medical Center at the University of California, Los Angeles in Los Angeles believe they have linked a gene mutation that regulates how potassium enters cells to a neurodegenerative disease and to another disorder that causes mental retardation and coordination problems. This discovery may lead to treatments for AD and Parkinson’s diseases. The team studied the KCNC3 gene which codes for one of the proteins that form potassium channels. These channels are pore-like openings in the cell membrane that control the flow of potassium ions into the cell. The KCNC3 gene codes for a type of potassium channel that opens and closes very quickly. This channel is important in fast-bursting neurons that fire hundreds of times per second in the brain. Dr. Pulst said “Fast-bursting neurons are like building blocks – they are used in the nervous system a lot.” Dr. Pulst said these channels also aid the motor control area of the brain called the substantia nigra, and the hippocampus where they play a role in learning. Earlier studies found abnormal-ities in the number of potassium channels in Parkinson’s, AD, and Huntington’s diseases. It is possible the potassium channel abnormalities may contribute to a wide variety of neuro-degenerative diseases. The research may lead to drugs that alter the activity of potassium channels. Dr. Pulst said in order to maximize the benefits and reduce side effects; researchers would need to find drugs that are specific for this type of channel. BestSyndication.com 2/27/06

Caregivers

Microsoft and DCU in AD R&D Venture - Software industry giant Microsoft has teamed up with a research team at Dublin City University (DCU) to jointly develop tiny cameras that can record a searchable digital picture diary of your entire day. It is envisaged the resulting technol-ogy could be an important aid forAD patients. Microsoft Research in Seattle has created a “SenseCam” - - a tiny camera combined with an “accelerometer,” a device that makes the camera aware of a person’s movements. These micro-cameras can be designed into jewellery, buttons or broaches to be unobtrusive or hidden. The micro-camera takes up to 3,000 digital pictures a day and is activated by the movement and activity of the wearer as well as the changing surroundings. DCU’s image and video search technology can then be used to analyse the 3,000 pictures and to isolate the highlights of the day. An important practical application of the research is for AD patients. With a SenseCam ‘day in the life’ diary, patients who may not be able to recall where they were or what they did will have an accurate record to consult. DCU’s professor of computing Alan Smeaton is leading the research. He explained: “We are very excited about this technology and about what it might offer for AD sufferers, their families and carers. It may also be used to track the development of the condition.” By John Kennedy SiliconRepublic.com 2/21/06

Testing

AD: Testing Times for Those at Risk - Long-term studies have shown biomarkers to be effective in predicting those with mild cognitive impairment that will go on to develop AD. Such a test could help companies developing new therapies for delaying or preventing the onset of AD, and, by identifying the need for treatment early, could improve both drug uptake and treatment success rates. A new study has shown certain cerebrospinal fluid (CSF) biomarkers to be able to predict whether a patient with mild cognitive impairment (MCI) will progress to AD. The findings bring a further ray of hope to new treatments aimed at preventing people from developing AD or dementia. The study, which was conducted at Sweden’s Lund University and published in The Lancet Neurology, measured levels of various CSF biomarkers in a sample of individuals with MCI - often thought to be related to an early form of AD. The root causes of AD may take hold decades before the symptoms become visible, meaning many preventative treatments may only have a chance to work if used in these early stages. In the study, the relative progression to AD in patients with MCI was substantially increased in those who had abnormal concentrations of b-amyloid, total tau, and phosphorylated-tau biomarkers in their CSF at the start of the study. The researchers followed the outcome of patients over four to five years and results revealed that 42% of patients with MCI developed AD, while 15% developed other types of dementia. The combination of markers identified incipient AD in patients with MCI with 95% sensitivity and 83% specificity. A lumbar puncture or spinal-tap is required to obtain CSF. The procedure takes five to 10 minutes, making it a longer procedure to perform than a blood sample. Furthermore, it requires local anesthetic and is associated with some additional, albeit rare, risks. The race is therefore on to discover similar markers in blood. Further long-term studies are required to validate the researchers’ findings. Results to date, however, suggest that the markers could provide a much needed means of detecting those individuals more likely to develop AD. Such a test would help drug manufacturers in trialing new treatments aimed at slowing or preventing the onset of AD. Pharmaceutical Business Newsonline 2/7/06 Lancet Neurology 2006;5:228-234

AD Blood Test a B.C. World First - A Vancouver neuroscientist who has developed the world’s first diagnostic blood test to detect diseases like AD, Parkinson’s, Lou Gehrig’s and mad cow disease says it should be available in a year or two. The test, which looks for clumps of misfolded proteins that underlie such diseases, was developed by Dr. Neil Cashman, an international expert on neurodegenerative diseases. In an interview, Cashman said the Epitope Protection technology, as it is called, can tease out clumps of aggregated misfolded proteins circulating in the bloodstream. “The test is sufficiently sensitive and specific as to be able to detect a minute amount of aggregated protein on a very large background of normal protein,” he said, referring to the fact that in AD, misfolded protein fragments accumulate in the brain as plaques that are “likely” released in the blood. The blood test would pick up those circulating protein fragments. Dr. Howard Feldman, head of neurology at UBC and Vancouver Hospital, said since “the finger has been pointed” at protein misfolding in many brain diseases, treatments in research are aimed at ways to remove such proteins. Diagnostic tests to detect such diseases early in illness are also important, he added. Feldman said any blood test will have to be reliable to 80 or 90 per cent specificity and sensitivity and it must be a test that laboratories, other than the proprietary ones, can replicate before doctors will use it and government approval can be achieved. By Pamela Fayerman Vancouver Sun 3/6/06

New Understanding Of Age-related Depression And Dementia Gained By Scientists - Researchers at the University of Edinburgh have identified for the first time a certain area of the brain which can shrink in old age and cause depression and AD. The scientists believe the shrinkage may be caused by high levels of stress hormones. They examined the size of a special region of the brain, the anterior cingulate cortex, that might be involved in controlling stress hormones. In a significant discovery, scientists found that people with a smaller anterior cingulate cortex had higher levels of stress hormones. Doctors analysed stress hormone levels and brain volume in two groups of ten healthy male volunteers aged 65-70 for the study. Lead author Dr Alasdair MacLullich said: “Doctors have known for several years that ageing, and certain diseases common in ageing like AD and depression, can be associated with shrinkage of the brain, but this is the first time we have been able to show that increased levels of stress hormones may cause shrinkage of this critical area of the brain. This is an important new finding because the anterior cingulate cortex shows damage in ageing, depression, and AD, and stress hormones are often high in these conditions. The discovery deepens doctors’ understand of ageing, depression and AD, and will help in the development of treatments based on reducing high levels of stress hormones.” Medical News Today 3/3/06 Possible related article is in Journal of Clinical Endocrinology & Metabolism with the abstract at http://jcem.endojournals.org/cgi/content/abstract/jc.2005-2610v1

Prevention

Physical Activity Promotes Brain Health - A recent research review identified 40 factors that may play a role in cognitive and emotional health, including education, cardiovascular health, physical activity and psychosocial factors. A panel of researchers reviewed 96 studies of adults who were predominantly 65 years and older in both Europe and North America. The review found that a growing body of observational research linked cognitive decline with several traditional risk factors for cardiovascular disease, including hypertension, greater body mass index, heart disease, diabetes and smoking. Physical activity was highly recommended for further investigation because a number of studies suggested a protective effect. If physical activity could be proven to protect against cognitive deterioration, it “would be of great public health importance because physical activity is relatively inexpensive, has few negative consequences, and is accessible,” the report said. A number of psychosocial factors-emotional and social support networks, high socio-economic status and low stress levels-correlated with cognitive and emotional health later in life. Some studies associated a history of depression or anxiety with poor cognitive and emotional health later in life. Chronic illnesses, such as arthritis, cancer, lung disease, heart disease and diabetes, were linked to poor emotional outcomes, specifically depression, in older people. “We found surprising consistency across the studies,” said panel member Marilyn Albert, PhD, from Johns Hopkins University School of Medicine. “In particular, we found that well-known risk factors for heart disease also are risk factors for cognitive decline, and that physical activity may reduce risk for cognitive decline and dementia in older adults.” TheMatureMarket.com 3/4/06 Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association, 2(1):12 (January 2006) For a full free copy go to http://www.alzheimersanddementia.org/current and click on Full Text or PDF

Preventive Maintenance For the Brain - If it seems you’re forgetting more as you grow older, you are. Like most other organs in the body, the brain gets smaller as we age, leading to a decline in memory, decision-making ability and verbal skills. That doesn’t necessarily mean that you’re on a steep downhill slide toward certain dementia, say experts. Growing evidence suggests there are steps you can take to better the odds of preserving your brainpower and protecting it against disease. Two avenues for boosting cognition -- challenging your brain and exercising your body -- have drawn considerable scientific research. Just last week a massive review of the scientific data, published online, found that getting lots of physical activity and reducing your risk of heart disease -- by cutting cholesterol and blood pressure levels, for example, or losing weight -- are among the best ways to maintain a healthy brain. The study (see item above), funded by the National Institutes of Health (NIH), also found that increased mental activity throughout life appears to preserve brainpower. By Alicia Ault Special to The Washington Post 2/21/06 See more discussion in the full article at http://www.washingtonpost.com/wp-dyn/content/article/2006/02/20/AR2006022001001.html

Also see online Live Discussion on this topic [Aging Preventive Maintenance for the Brain] by Dr. Molly V. Wagster on February 21, 2006 at http://www.washingtonpost.com/wp-dyn/content/discussion/2006/02/17/DI2006021701615.html

Vitamin E: No Disease Prevention Benefit, Possible Risks - More is not necessarily better when it comes to vitamin E, according to the March issue of Mayo Clinic Women’s HealthSource. Vitamin E is an antioxidant that protects body tissue from damage caused by unstable substances called free radicals. Free radicals can harm cells, tissues and organs, and they are believed to be one cause of the degenerative processes seen in aging. For years this popular antioxidant was thought to offer protection against heart disease, cancer, AD and cataracts. But in more recent clinical trials, the strongest form of scientific proof, researchers were unable to show that vitamin E offers a clear benefit in terms of disease prevention. A recent analysis of 19 clinical trials suggests that too much of the vitamin - - 400 international units (IU) or more - - may actually increase health risks. But all the answers aren’t in yet. Several studies are in progress to see if low levels of vitamin E may offer some protection against illness. In the meantime, it’s best to get most of your vitamin E from dietary sources. Options include almonds, sunflower seeds, safflower and corn oil, hazelnuts, tomato sauce, peanuts, mangos, kidney beans, spinach, kiwi and broccoli. If you decide to take a supplement, don’t take more than 400 IU daily unless directed by your doctor. Newswise 3/4/06

Other Items

Neuronal Receptor Response May Help Explain AD Memory Loss - Based on laboratory research, scientists at Georgetown University Medical Center have a new theory as to why people with AD have trouble performing even the simplest memory tasks, such as remembering a family member’s name. That’s because they discovered a physical link between apolipoprotein E (APOE), the transport molecules known to play a role in development of the disease, and glutamate, a brain chemical necessary for establishing human memory. The research team specifically found that receptors on the outside of brain nerve cells (neurons) that bind on to APOE and glutamate are connected on the surface of neurons, separated from each other by only a small protein. While the researchers don’t know why these receptors are linked together, they say inefficient or higher-than-average levels of APOE in the brain could possibly be clogging these binding sites, preventing glutamate from activating the processes necessary to form memories. “We have found out that two receptors previously thought to have nothing to do with each other do, in fact, interact, leading us to conclude that APOE affects the NMDA glutamate channel that is important in memory,” says the study’s senior author, G. William Rebeck, PhD, associate professor of neuroscience in Georgetown’s Biomedical Graduate Research Organization. The researchers also hypothesize that this interaction might have something to do with development of AD, although they stress that at this early stage of research, this is impossible to prove. APOE is a protein that helps shuttle cholesterol and other non-soluble lipid particles around the body, moving these substances to where they are needed. All cells have receptors that bind on to APOE so that they can use lipids as needed, such as for quick energy, to store as fat for later use, or to repair wounds. Science Daily 2/10/06 Journal of Biological Chemistry, 281(6) 3425-3431 Feb 10, 2006

AD Progresses Faster in Educated People - High levels of education speed up the progression of AD, according to a study published in the March issue of the Journal of Neurology, Neurosurgery and Psychiatry. Mental agility dropped every year among AD patients with each additional year of education, leading to an additional 0.3 percent deterioration, the researchers from the Columbia University Medical Center in New York found. The speed of thought processes and memory were particularly affected. Previous studies have shown that people with high levels of education are less likely to develop AD. The new study shows that the brains of more educated people can tolerate changes for longer periods of time, meaning signs of decreased mental agility typical of AD disease appear later. When those signs do appear, the disease progresses faster than it does in less educated patients. “The amount of nerve connections and information hubs are likely to be more numerous and more efficient in people who are highly educated,” said lead author Nikolaos Scarmeas in his study. “The subsequent impact is likely to be greater than it would be in less educated brains, because of the higher levels of accumulated damage.” The findings are based on the study of 312 New Yorkers aged 65 and older, who were diagnosed with AD and monitored for more than five years. All the patients underwent around four neurological assessments, each of which comprised a dozen separate tests of brain function. The level of the drop-off was particularly evident in the speed of thought processes and memory, Scarmeas said. The result didn’t depend on age, mental ability at diagnosis or other factors likely to affect brain function, including depression and diseases of the blood vessels. Bloomberg 2/16/06 Journal of Neurology, Neurosurgery and Psychiatry, 2006, 77:308-316

Depression and AD - Two studies in the same issue of the Archives of General Psychiatry addressed another continuing debate: Whether depression increases the risk of developing AD. And they seemed to arrive at conflicting results. One study, led by Dr. Michael A. Rapp, a researcher at the Alzheimer’s Research Center of Mount Sinai School of Medicine in New York City, included 95 AD patients in nursing homes. It found that those with a history of depress-ion had a higher number of AD-associated plaques and tangles in their brains. “We found that depression might affect cognitive decline over time, but further studies are needed,” Rapp said. The other study followed nearly 1,300 adults over the age of 67 for 12 to 15 years. Every two years, the researchers looked for evidence of depression as well as any decline in mental function. Having depression at the start of the study did not predict the onset of AD, the researchers found. “What we concluded is that if a clinician sees a patient who is both depress-ed and cognitively impaired, the impairment may be related to the depression, [but] if the person’s impairment continues to progress over time, it is not due to the depression,” said lead researcher Dr. Mary Ganguli, a professor of psychiatry and epidemiology at the University of Pittsburgh. The study did show that depression is associated with poor mental function, “but we’ve known that for some time,” Thies said. “People with poor memories tend to be depressed.” HealthDay News 2/7/06 Archives of General Psychiatry, 2006;63:153-160 (Ganguli) & 161-167 (Rapp)

Ashe, LaFerla, Haass Win 2006 MetLife Awards - The MetLife Foundation announced this year’s award winners at a celebration of its 20 years of funding innovative AD research. Karen Ashe, of the University of Minnesota Medical School in Minneapolis, won the 2006 MetLife Award for Medical Research in AD for her work on mouse models of AD. Frank LaFerla, of the University of California, Irvine, won a Promising Work Award for his triple-transgenic model, as did Christian Haass, of Ludwig-Maximilian University in Munich, Germany, for his studies of the cell biology and mechanism of action of γ-secretase. Nearly half-million dollars will be used by the recipients to further their work. By Gabrielle Strobel Alzheimer Research Forum 2/20/06 See Frank LaFerla’s new drug AF267B in the Drugs section

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