Alzheimer Related News Items

                 News as of 5/07/06 –NOTE: new e-mail address

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Top Items

HMS Seeks AD Vaccine - Nose drops developed by Harvard Medical School researchers have impeded the development of AD in mice, and an AD nasal spray for humans could be on the horizon. While plaques made up of beta-amyloid proteins accumulate in the brains of AD sufferers, the new vaccine allows the immune system to produce antibodies that fight these proteins. In tests that have are detailed in the Journal of Neuroscience, the vaccine significantly diminished plaques on the brains of treated mice. Ultimately, researchers would like the new vaccine to be tested on humans, according to one of the study’s authors, Cynthia A. Lemere, who is an associate professor of neurology at the Medical School and an associate neuroscientist at Brigham and Women’s Hospital in the Center for Neurologic Diseases. “We would very much like to take one of our short-immunogen vaccines into human clinical trials,” Lemere said. “But we’re still working on refining it.” On mice, the vaccine was administered in the form of nose drops, and it would likely appear in the form of a nose spray if it were to become widely available. “That’s one of the things that distinguishes our vaccine from the others,” Lemere said. “Typically when you immunize through the nose, you get more of an anti-inflammatory response.” “We’re working on a skin patch type of vaccine as well,” Lemere added. While the spray would be “most effective at prevention,” Lemere said, one of the key features of the vaccine is that it “will probably also have very good effects at stopping the progression of the disease at early stages.” There is some dispute, though, as to the effect that the vaccine will have on those who have been suffering from AD for a significant amount of time. “It won’t have a good effect on reversing the disease once there is cell damage,” Lemere suggested. “But there are people in the field who do think that even in very demented people that there is a chance that they would show some improvement.” The most likely people to receive the vaccines first would be those whose family members suffer from the disease. “Those people would be very good candidates for a vaccine,” Lemere said. “They don’t really have a lot of alternatives - - once they have that mutation, the probability of them getting AD is extremely high.” By Kevin C. Reyes Contributing Writer The Harvard Crimson 5/5/06 Journal of Neuroscience, May 3, 2006, 26(18):4717-4728

Diabetes Drug Might Slow AD Onset - A provocative new theory suggests that one root cause of AD is diabetes. To test that theory, the maker of the diabetes drug Avandia plans to give it to thousands of AD patients in hopes of slowing brain decay. The proponents hope that if diabetic-like changes in the way brain cells use sugar to generate energy truly trigger AD, then maybe doctors could intervene early and slow that degeneration. A preliminary experiment involving 511 AD patients showed Avandia might help -- although those patients lacked the APOE4 gene that spurs more aggressive AD. Those results have Avandia maker GlaxoSmith-Kline poised to open three Phase III clinical trials this summer to test whether the diabetes drug, also called rosiglitazone, might protect certain patients’ brains. Diabetes has long been listed as a risk factor for AD because it damages blood vessels that supply the brain. The Avandia research suggests that AD can be silently triggered when brain cells can’t properly use their main fuel, sugar -- just as type 2 diabetes is triggered when insulin gradually loses its ability to process sugar body-wide. If it pans out, “one thing we can do is, possibly, slow down the onset of the disease showing up,” said Glaxo Vice President Allen Roses. But for now, “it’s a hopeful experiment that’s in progress.” By Lauran Neergaard AP 5/2/06 Article by Alan Roses in Alzheimer’s & Dementia, 2(2):59-70 (April 2006)

Drugs

MIT Research Offers New Hope For AD Patients, Cocktail Of Dietary Supplements, Now In Human Clinical Trials - MIT brain researchers have developed a “cocktail” of three dietary supplements (omega-3 fatty acids, uridine and choline), now in human clinical trials, that holds promise for the treatment of AD. These compounds are all needed by brain neurons to make phospholipids, the primary component of cell membranes. For years, doctors have encouraged people to consume foods such as fish that are rich in omega-3 fatty acids because they appear to improve memory and other brain functions. The MIT research suggests that a cocktail treatment of omega-3 fatty acids and two other compounds normally present in the blood, could delay the cognitive decline seen in AD. After adding those supplements to the diets of gerbils, the researchers observed a dramatic increase in the amount of membranes that form brain cell synapses, where messages between cells are relayed. Damage in brain synapses is believed to cause the dementia that characterizes AD. If the successful results obtained in gerbils can be duplicated in the ongoing human trials, the new treatment could offer perhaps not a cure but a long-term AD treatment similar to what L-dopa, a dopamine precursor, does for Parkinson’s patients, said Richard Wurtman, a professor in the Department of Brain and Cognitive Sciences. “It doesn’t cure Parkinson’s, but what it does do is to help replace something that’s missing. It’s not permanent, but it has had an enormous impact on people who have Parkinsons,” he said. The new potential treatment offers a different approach from the traditional tactic of targeting the amyloid plaques and tangles that develop in the brains of AD patients. Instead, the new research focuses on brain synapses, where neurotransmitters such as dopamine, acetylcholine, serotonin and glutamate carry messages from presynaptic neurons to receptors in the membranes of postsynaptic neurons. In AD patients, synapses in the cortex and hippocampus, which are involved in learning and memory, are damaged. After the dietary supplements were given, the researchers detected a large increase in the levels of specific brain proteins known to be concentrated within synapses, indicating that more synaptic membranes had formed, Wurtman said. Synaptic membrane protein levels rose if the gerbils were given either omega-3 fatty acids or uridine plus choline. However, the most dramatic upsurge was observed in gerbils fed all three compounds. Medical News Today 4/28/06 published 4/26/06 online Brain Research doi:10.1016/j.brainres.2006.03.019

Genes & Genetic Issues

New Genetic Cause Of AD Discovered - Researchers from the Flanders Interuniversity Institute for Biotechnology (VIB) connected to the University of Antwerp are the first to show that the quantity of amyloid protein in brain cells is a major risk factor for AD. Amyloid protein has already been known to be the primary component of the senile plaques in the brains of patients. The new discovery demonstrates that the greater the quantity of the protein that is produced, the younger the dementia patient is. Genetic research has previously shown a direct connection between amyloid protein and the development of senile plaques and loss of cells. Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases (fewer than 1 in 1000 patients), mutations appear in that amyloid precursor protein, causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. The development of amyloid plaques in the brain tissue of AD patients is a central factor in the search for a therapy for AD. The fact that patients with Down syndrome get AD shows that the quantity of the amyloid precursor protein contributes to the disease: in fact, patients with Down syndrome have 3 copies of the gene (or hereditary code) for the amyloid precursor protein and therefore produce 150% instead of 100% of the protein. So, Jessie Theuns and her colleagues, under the direction of Christine Van Broeckhoven, hypothesized that the quantity of amyloid precursor protein might also play a role in AD. The geneticists from Antwerp systematically studied the hereditary code that is responsible for controlling the expression of the gene (= promoter). Biological processes in our body are strictly regulated, primarily by closely controlling the amount of each protein that is produced. The promoter of a gene has the most important control function in this process. In younger Belgian and Dutch AD patients (younger than 70), the researchers found genetic variations in the promoter that increased the gene expression and thus the formation of the amyloid precursor protein. These variations in the promoter that increase expression occur up to 20 times more frequently (2 per 100 patients) than the mutations in the precursor protein that change the shape. Furthermore, there is a connection with the age at which the symptoms are first detected: the higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for AD in the ageing process. These new findings lead to a new understanding: namely, that the quantity of the amyloid precursor protein, and thus of the amyloid protein, in brain cells contributes significantly to the risk of contracting AD. This discovery will have to be taken into account in diagnostic tests and in the search for new medicines. Medical News Today 4/22/06 Amercan Journal of Human Genetics, 78:936-946, June 2006

Caregivers

Full Social Lives May Protect Against AD - Social networks -- such as having close friends and staying in contact with family members -- help protect against the damaging effects of AD, a new U.S. study finds. “Many elderly people who have the tangles and plaques associated with AD don’t clinically experience cognitive impairment or dementia,” Dr. David A. Bennett of the Rush University Medical Center’s Alzheimer’s Disease Center, Chicago, said in a prepared statement. “Our findings suggest that social networks are related to something that offers a ‘protective reserve’ capacity that spares them the clinical manifestations of AD,” he said. The study included 89 elderly people without known dementia taking part in the Rush Memory and Aging Project. While they were alive, each provided information about their social networks and underwent 21 cognitive performance tests each year. After they died, their brains were analyzed. The larger a person’s social network, the less effect the tangles and plaques had on their cognitive test scores. This protective effect was noted across different kinds of cognitive abilities but was most evident for semantic memory, which contains knowledge about the world and is involved in language and other uniquely human cognitive processes. HealthDay News 4/28/06 The Lancet Neurology 5(5), May 2006, pg 406-412

Testing

Brain Scan May Spot AD Before Symptoms - A new study has identified structural and metabolic brain changes that may predict dementia or cognitive decline in normal older adults. Furthermore, the anatomical location of these changes suggests AD pathology. To determine if brain imaging could identify predictors of dementia in people with normal mental function at baseline, researchers followed 60 Latino individuals who were 60 to 100 years old for an average of 4 years. The subjects underwent examination with two imaging techniques -- positron emission tomography or PET imaging and magnetic resonance imaging or MRI. At follow-up, six subjects developed cognitive impairment or dementia. According to Dr. William Jagust of the University of California at Berkeley and colleagues, there was a “high positive correlation” between faster declines in cognitive function on a standard test and lower glucose metabolism in key areas of the brain. The pattern of glucose metabolism, together with the location of brain regions that are predictive of AD “suggests that these findings are due to the detection of presymptomatic AD,” the researchers conclude. Reuters Health 5/1/06 Annals of Neurology 59(4):673-681( April 2006)

Prevention

Nutrition: Mediterranean Diet Looks Good for AD - The Mediterranean diet, high in monounsaturated fat and low in meat and dairy products, appears to reduce the risk for AD, according to a study of a New York City population, and the more strictly it is adhered to, the stronger its preventive effect. The researchers studied 2,258 Medicare recipients in Manhattan who did not have dementia, recording their health status and their consumption of constituents of the Mediterranean diet: olive oil, fruits, vegetable, legumes, cereals, fish, a little alcohol and very little dairy or meat. Researchers classified the subjects by how strictly they followed the diet. Over the next four years, 262 participants developed AD. The third who were most faithful to the diet were 40 percent less likely to develop AD than the third least faithful, and the third who were moderately compliant were 15 percent less likely to develop it. The authors, led by Dr. Nikolaos Scarmeas, an assistant professor of neurology at Columbia, acknowledged the study’s weaknesses. Still, Dr. Scarmeas said, “The findings are very strong, and they make biological sense. This diet is associated with lower rates of cardiovascular disease, lower oxidative stress and lower inflammation, which have in turn been associated with lower risk for AD.” Should everyone go on the diet? Maybe not yet. “Ultimately,” Dr. Scarmeas said, “recommend- ations have to come from similar findings in repeated observational studies like this one, and, if feasible, from clinical trials.” By Nicholas Bakalar NYTimes 4/25/06 Annals of Neurology published online 4/18/06 doi:10.1002/ana.20854

Other Items

Study: Cellular origins of AD - Breakthrough discoveries are pushing back the origins of to an early breakdown in trafficking within brain cells, according to researchers at the Weill Medical College of Cornell University in New York City. Experts have long known that a buildup of beta-amyloid protein “plaques” around and between neurons is a hallmark of AD. But they’ve also known that neurological decline can occur prior to this extra-cellular buildup. “Our work is showing that long before this extracellular phenomenon occurs, beta-amyloid is building up inside neurons - - specifically, on intracellular trafficking structures called multivesicular bodies,” explained Gunnar Gouras, M.D., director of the Laboratory of AD Neurobiology and associate professor of neurology and neuroscience at Weill Cornell Medical College. “In our latest study - - conducted using brain cells from mice engineered to develop an AD-like illness - - we find that this gradual accumulation of beta-amyloid hinders the intracellular trafficking of neural receptors in a very specific way,” he said. “The brain cell isn’t killed, but it is impaired in its function. And all of this occurs long before we see any evidence of plaque buildup outside the cell,” Gouras said. He said the work is greatly expanding our understanding of the origins of AD, and pointing to new ways to fight it. “We now know that intracellular beta-amyloid buildup is associated with a destruction of specific processes within nerve cells - even in the absence of extracellular plaque accumulation,” Gouras said. The finding “opens a new window on the causes of AD and - potentially - new targets that researchers might focus on to help prevent it in its earliest stages,” he added. myDNA News 5/4/06 Journal of Neuroscience, April 26, 2006, 26(16):4277-4288

OHSU Research Reveals Possible Future Target for Delaying or Stopping AD - Researchers at Oregon Health & Science University’s Neurological Sciences Institute (NSI) have located a possible target for future therapies aimed at delaying or stopping AD. “This research more clearly demonstrates how structures, called mitochondria, in brain cells are a key part of the disease process in AD. In fact, mitochondria appear to be a site where significant disease progression takes place,” explained P. Hemachandra Reddy. “We also believe that toxins produced by the mitochondria contribute to AD progression. In other words, the entire system may be one big feedback loop. Therefore, it is possible that therapies which encourage normal mitochondrial function may in fact delay or stop the disease in its early stages by breaking the loop.” To conduct the research, Reddy and his colleagues studied mice that are bred to have an AD-like neurodegenerative disease. Like human AD patients, the brains of these mice produce elevated levels of amyloid precursor protein (APP). They also develop formations called beta amyloid plaques. By observing mitochondrial function in brain cells of these mice, Reddy and his colleagues determined that beta amyloid could be found both inside and outside of the mitochondria. Because mitochondrial oxidative damage is a hallmark of AD, the scientists believe the higher accumulations of these substances may be responsible. In addition, the scientists found increased levels of hydrogen peroxide in the AD mice, likely produced by the mitochondria due to the oxidative damage. “We believe that the disease produces mutant APP and beta amyloid which in turn impacts mitochondrial function. This results in increased production of hydrogen peroxide, resulting in a progression of the disease and higher levels of beta amyloid,” said Reddy. “In other words -- this model appears to be a vicious cycle where damage to brain cells increases and in fact feeds upon itself.” PR 5/1/06 Human Molecular Genetics 15(9):1437-1449

Cerebral Emboli More Common in Demented Patients - Cerebral emboli are significantly more common in patients with AD and vascular dementia than in their healthy counterparts, according to a report in the British Medical Journal. Given these findings, cerebral emboli “may represent a potentially preventable or treatable cause of dementia,” senior author Dr. Charles McCollum, from the University of Manchester in the UK, and colleagues comment. In the new study, Dr. McCollum’s team used transcranial Doppler to assess the occurrence of spontaneous cerebral emboli in 85 patients with AD, 85 patients with vascular dementia, and in 150 matched controls. Cerebral emboli rates for patients with AD and vascular dementia were 40% and 37%, respectively. By contrast, among controls, the rate was around 14%. “This study is the first to show an association between spontaneous cerebral emboli and dementia,” the investigators state. “The similar frequency of emboli in both types of dementia suggests a common cause and shared pathophysiology.” Reuters Health 4/27/06 BMJ published 4/28/06 doi:10.1136/bmj.38814.696493.AE

Reversal of AD Cognitive Decline by New Treatment Suggested in Small Human Pilot Study - A six-month, open-label, uncontrolled pilot study in which 15 patients with AD ranging in severity from mild to severe received weekly perispinal injections of etanercept, a medication designed to reduce excess levels of tumor necrosis factor (TNF). TNF is a molecule which initiates and amplifies the inflammatory response in the brain and other organ systems. Dr. Hyman Gross at UCLA noted, “So far this appears to be the most effective treatment for the reversal of some of the major symptoms of AD. I have recommended that my patients continue on this treatment, as without it they continue to cognitively decline. Large scale clinical trials should begin immediately to define its most appropriate therapeutic use.” The pilot study discussion includes in-depth analysis of how this innovative method of anti-TNF treatment may reduce inflammation in the AD patient’s brain. An increasing body of research points to inflammation as a critical factor in the pathophysiology of AD. Previous work by Elizabeth Tarkowski and her colleagues at the University of Goteborg in Sweden documented levels of TNF 25 times elevated in the cerebrospinal fluid (the fluid surrounding the brain) in patients with AD. Etanercept is FDA approved for treating rheumatoid arthritis and related conditions, but is off-label for treating AD. The new study suggests that perispinal etanercept may have the potential to improve cognition when added to standard therapy consisting of memantine and/or a cholinesterase inhibitor. “There is an enormous unmet medical need in AD, an incurable, terminal and devastating affliction for the patient, as well as for families and society in general,” stated Dr. Hart Cohen at UCLA. “We should take these findings very seriously and confirm them in broader trials initiated immediately.” Genetic Engineering News 4/28/06 Posted 4/26/06 in the neurology section of the journal Medscape General Medicine, 2006;8(2):25 Copy of full article at http://www.medscape.com/viewarticle/529176_1

Sticky Brains Don’t Dull Memories - Plaque on the brain doesn’t sound good, but the condition may not be as crippling as once thought. Mice with the gummy deposits-- usually a symptom of AD - - can still have normal memories, according to a new study. The findings suggest a novel target for AD drugs and a new way of understanding how the disease ravages the brain, say the researchers. AD is thought to be caused in part by sticky build up of a toxic peptide called β amyloid, produced when the amyloid precursor protein (APP) is cut in two. Recent research, however, has shown that early signs of the disease are present even before these plaques show up in the brain. When APP is cut at another point, a different protein, called C31, is released. It too has toxic properties, but until now, its role in AD has been a mystery. Neuroscientists led by Veronica Galvan and Dale Bredesen of the Buck Institute for Age Research in Novato, California, decided to examine what would happen when mice were prevented from making C31. They used a strain of mice that gets AD-like symptoms and bred them so that APP couldn’t be cut into C31. Although the animals could still make β amyloid and plaques, other signs of AD were absent. For one, their brains were a normal size and contained a higher density of neuronal synapses compared to the shrunken brains of C31-producing mice. And they did twice as well on a standard test for memory in mice. Bredesen++

“We have been looking at AD as a disease of toxicity,” he says. But the new findings make it look more like a disease of misfired cellular signals, he says. Bredesen says preventing the snipping of C31 could be an effective strategy in avoiding the memory loss and brain damage of AD. By Katherine Unger ScienceNOW Daily News 4/24/06 Proceedings of the National Academy of Sciences 5/2/06 vol. 103, no. 18 7130-7135

Survey of Baby Boomer Attitudes on AD - First major survey of baby boomer attitudes on AD shows fear about their own future and frustration over pace of new drug approvals. The new survey shows the majority of Boomers are anxious about how AD will affect their health and quality of life. At the same time, Boomers are frustrated that the government and the U.S. Food and Drug Administration (FDA) do not adequately address adequately this looming public health crisis. The findings from the first major survey of over 1,000 American Baby Boomers about AD were announced 5/2/06 by a newly formed coalition of 21 leading advocacy groups known as ACT-AD (Accelerate Cure/Treatments for Alzheimer’s Disease). “These survey findings underscore the fact that when Baby Boomers are asked to address the potential of AD in their future, they are clearly not ready emotionally, psychologically or financially,” said Daniel Perry, executive director of the Alliance for Aging Research and chair of the ACT-AD Coalition. “Many Boomers are currently more focused on health issues like heart disease or arthritis and mistakenly consider AD a problem of their elders. But when asked to consider themselves at age 70 with AD, there was a visceral reaction and an awakening to the reality of what could await them. They also have little confidence that policymakers, the US healthcare system, or drug regulators are prepared to help them. As the crisis looms, ACT-AD will press ahead for a solution.” The Maturemarket.com 5/2/06 ACT-AD website is http://www.ACT-AD.org

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