Alzheimer Related News Items

News as of 09/05/04

For more info on these abstracts write/call Ed Cabic (edcabic@comcast.net or 410-992-7197)

For more AD information, see Alzheimer Information athttp://www.connext.net/~seniors/infoad.htm

Copies of these reports are posted there

This web page was started at the Florence Bain Senior Center in Columbia MD

NOTE: There was no Report for August 2004

Top Items

AD Focuses on Brain Buildup - How to prevent a sticky gunk from clogging up, and probably killing, the brain cells of AD patients is the newest focus in the fight against the disease. Half a dozen companies are developing drugs to target the buildup, and researchers are enrolling hundreds of patients to test the lead candidate -- although nobody yet knows if this gunk, called beta-amyloid, is the disease’s true culprit. Different attempts to attack that plaque are described:

 * Beta-amyloid initially floats in the blood and spinal fluid, until the sticky substance bonds with helper molecules to form chains that build into plaque. Alzhemed essentially coats beta- amyloid, reducing the stickiness so those chains can’t form. A Phase III study is enrolling about 500 patients around the country and in Canada to try to prove Alzhemed’s effects.

* Lilly hopes to halt beta-amyloid formation in the first place. Its drug candidate blocks an enzyme called gamma secretase. The enzyme helps create beta-amyloid by clipping pieces that form it off a larger protein. In early studies, AD given the still-unnamed drug for six weeks had a 40 percent reduction of beta-amyloid in their blood. Lilly is pursuing additional small studies, but can’t yet say when large-scale testing may begin.

* Merck & Co. is trying to block another enzyme, beta secretase, also involved in amyloid formation.

* New York-based Axonyx has Phase III studies under way in Europe of a drug called phenserine. It targets a symptom-causing brain chemical like older AD drugs do, but also may have the added boost of somehow lowering beta-amyloid production.

* Wyeth Pharmaceuticals and Elan Corp. have begun early human studies of antibodies, immune system cells created to attack existing amyloid plaque. Elan’s earlier attempt at a vaccine to spur patients’ own immune system to do the job failed when some suffered serious brain inflammation.

* Harvard researchers are studying whether drugs that remove copper from the body may also remove amyloid. These approaches require years more research. Meanwhile, there are some steps that may help prevent AD said Dr. Mark Mattson of Johns Hopkins University: Exercise and avoid obesity, high cholesterol and high blood pressure, because the same things that cause heart disease seem to play a role AD in. And keep mentally active, too -- it likely protects brain cells. By Lauran Neergaard AP Medical Writer 9/6/04

Study: Drug Might Delay AD - People with a common memory disorder, Mild Cognitive Impairment or MCI, that often leads to AD may be able to briefly delay that fate by taking a drug normally prescribed for AD indicates a new study presented at the 9^th International Conference on AD. But ultimately the drug Aricept doesn’t cut the risk of getting the feared illness, despite an average delay of six months. The lead author of the study, Dr. Ronald Petersen of the Mayo Clinic, said it was too early to make any recommendations for doctors and patients. He called the new results “a foot in the door” to finding more effective treatments. The same study found no effect from vitamin E, long viewed as a possible weapon against AD.

The experiment is the first to show that AD can be delayed in people with MCI, Petersen said. So researchers might be able to find other treatments that will produce more than the “modest” effect of Aricept, he said. Bill Thies, vice president for medical and scientific affairs of the Alzheimer’s Association, said vitamin E “is used by almost anyone who’s worried about AD,” whether because of a family history or a sense of slipping memory, and users will probably continue to take it despite the study’s finding. AP 7/19/04

Drugs

New Thinking About AD Treatment - There are only five drugs approved by the FDA specifically for treatment of AD, and only four are widely used (the fifth, Cognex, has serious side effects and has largely fallen out of use). But because they work on the symptoms of AD-- memory loss, confusion, agitation -- rather than on the actual pathology that causes the symptoms, these drugs may be a case of too little, too late. “Everybody feels like we have to do something about this disease fast. The numbers of people who are going to be affected by it is so great, we know what a difference it could make if we could delay onset even by five years. And we also know that the disease takes a long time to evolve in the brain, so the sooner we intervene, the better,” says Marilyn Albert, PhD, director of the division of cognitive neuroscience in the department of neurology at Johns Hopkins University School of Medicine in Baltimore. The first brain changes of AD may occur as early as 10 to 20 years before the first symptoms of the disease appear, Bengt Winbald, MD, PhD, professor of geriatric medicine and chief physician at the Karolinska University Hospital and Karolinska Institute in Stockholm, Sweden, tells WebMD. Until recently, those changes have been too small or too subtle to easily detect, making it extremely difficult to identify people who could benefit from early intervention.

But that appears to be changing. A key theme at this year’s AD conference is advances in brain imaging that may make it possible to detect and diagnose early AD, leading to the development of drugs and other treatment strategies that could halt or at least slow the progression of disease. One of the most intriguing strategies discussed at this year’s conference involves drugs or vaccines aimed at clearing deposits of an abnormal form of a protein that accumulates in the brains of people who suffer from AD. The protein, known as beta amyloid, forms clumps or “plaques” and is a hallmark of AD. One experimental drug, called Alzhemed, has been shown in animal and human studies to clear significant amounts of beta amyloid deposits from the brain. A similar drug, known only as LY450139, has shown similar effects in humans. Several companies are also working on vaccines that can stimulate the body to make antibodies that attack and dissolve beta-amyloid deposits. Other experimental drugs and vaccines are aimed at treating another suspected cause of AD, a different protein known as tau, which normally serves as a building block of nerves. In the brains of people with advanced AD, strands of twisted tau proteins, called fibrillary tangles, can be found inside brain cells. But whether beta amyloid and tau are the causes of AD or a result of it is still unclear. By Neil Osterweil Webmd.com 7/23/04

Two AD Drugs Show Potential - Two experimental AD drugs have the potential to prevent or halt the progress of the brain-wasting disease, doctors said on 7/21/04. Both focus on beta- amyloid, a protein that is suspected of causing AD. It accumulates into the characteristic clogs called plaques that distinguish the brains of people who have died from AD. In one study at Georgetown University Medical Center in Washington, 58 people with mild to moderate AD took a drug called Alzhemed or a placebo for three months, then for an additional 21 months. Alzhemed, made by Montreal, Canada-based Neurochem Inc., is a pill just beginning Phase III trials, the final stage before a company seeks approval from regulators for a new drug. The study, reported at a meeting of AD experts in Philadelphia, found a significant drop in the level of beta-amyloid among patients who took the drug and no change among those taking the placebo. The researchers also found Alzhemed in cerebral spinal fluid, which indicates it was finding its way to the brain where it is needed. The drug reduced the levels of beta-amyloid in the spinal fluid and was generally safe and well tolerated, the researchers found. In another study, Eli Lilly & Co. is trying to prevent beta-amyloid from forming in the first place. A trial of 37 healthy adults aged over 45 found blood levels of beta-amyloid were reduced after they took LY450139, an experimental drug designed to interfere with the formation enzymes called secretases, which generate beta-amyloid. The trial found reduced levels of beta-amyloid in the blood after the drug was administered. Higher doses produced a greater reduction. Although the drug was detected in cerebral spinal fluid, it did not reduce concentration of beta-amyloid in the fluid. Researchers need to know the most effective dose before starting a larger trial, said Dr. Eric Siemers of Eli Lilly. By Jon Hurdle Reuters 7/22/04

Anti-hypertensives May Reduce AD Risk - Anti-hypertensive drugs appear to offer protection against the onset of AD, and some are associated with a slightly greater risk reduction for the disease than others, according to a presentation here at the ninth International Conference on AD. The findings come from the Cache Country Study in Utah, a long-term population survey that began in 1995. “Our first finding was that among the anti-hypertensive medication users, there was about a 36% risk reduction in incident AD,” compared with people who were not on the medications, said investigator Dr. Ara Khachaturian (PhD). Diuretics stood out as being associated with a slightly greater risk reduction for the development of AD over other anti-hypertensives. “When we restricted it to individuals who used any diuretic, the risk reduction was approximately 40%,” he said. When other possible cofounders were taken into account such as age, sex, education, the number of APOE e4 alleles and history of diabetes, heart disease or stroke, anti-hypertensives were still associated with an apparent reduction in risk for AD. However, Dr. Khachaturian cautioned that people should not consider anti-hypertensive medication as a preventive for AD. By Pippa Wysong The Medical Post 8/10/04

New Treatments for AD Symptoms - Geriatric psychiatrists are using a host of new medications to treat the personality changes and aggression that often accompany AD - including drugs generally used to treat schizophrenics. While most people associate AD with the slow erosion of memory, about half of all sufferers also develop psychiatric and behavioral symptoms, including violent outbursts, paranoid thoughts and intense anxiety. Doctors have tried treating such symptoms with tranquilizers and early antipsychotic drugs, but these approaches were either overly sedating or produced dangerous side effects, and health-care providers have been pressured to reduce their use. Now, a number of new studies show that so-called atypical antipsychotics, a class of drugs normally used to treat young schizophrenics, can reduce the psychiatric symptoms of AD and other kinds of dementia. Studies also show that some anticonvulsant medications used for epilepsy also may help. The National Institute on Aging is funding a trial looking at whether one anticonvulsant, Depakote, will actually prevent those with mild to moderate AD from developing psychiatric symptoms at all. Some of these drugs - which include the antipsychotics Zyprexa from Eli Lilly & Co. and Risperdal from Janssen Pharmaceutica - carry serious side effects of their own, including an increased risk of stroke and diabetes. And they aren’t approved by the Food and Drug Administration for use in AD. But doctors have been increasingly prescribing them to AD “off-label,” and they say the risks of side effects are much lower than with older treatment options. Doctors and patients are desperate to do something about the devastating psychiatric symptoms of AD. Psychiatrists say that behavioral issues and violent outbursts - not memory loss - are the primary reasons family members send loved ones with AD to a nursing home. By Andrea Petersen The Wall Street Journal 8/26/04

Stopping AD: Antibody Thwarts Disease in Mice - Scientists working with mice report 8/5/04 that antibodies tailor-made to attack amyloid can wipe it out and reverse an experimental version of AD if the intervention begins early enough. What’s more, removing amyloid rubbed out its partner in crime, a protein called tau that collects in tangles inside brain cells. This study “provides the strongest experimental evidence to date” that amyloid is the ringleader of AD, says coauthor Frank M. LaFerla, a neuroscientist at the University of California, Irvine. LaFerla suspects that amyloid collaborates with tau to kill neurons and trigger the confusion and memory loss that mark the disease. In their tests, LaFerla and his colleagues used mice genetically engineered to make excess amyloid and tau. The researchers then injected antibodies against amyloid into the animals’ brains. Three days later, the researchers could not find any amyloid plaques in the brain region targeted by the injection, but neurons there still contained tau tangles. After 2 more days, these tangles were cleared too. “This is an important paper,” says David Morgan, a neuroscientist at the University of South Florida in Tampa. Knocking out amyloid plaques and subsequently seeing a decrease in tau indicates that the plaques promote tau tangles in the brain, he says. “This shows that there is an early window of time during which clearance of amyloid by antibodies is accompanied by clearance of tau,” says neurologist Sam Gandy of the Thomas Jefferson University in Philadelphia. Morgan says the finding indicates that antibody therapy might work best if administered early in the disease. By Nathan Seppa Science News Online 8/7/04 Neuron, vol 43,321-332, 5 Aug 2004

Cancer Drug Could Help AD - A drug being tested to treat cancer, bryostatin, also might be used to slow memory loss and the cause of AD, according to a West Virginia researcher. “This is the first therapy to have two major benefits. It provides symptomatic relief from the memory loss of AD and protects against the degeneration of the neurons that causes the memory loss,” said Dr. Daniel Alkon, scientific director of the Blanchette Rockefeller Neurosciences Institute in Morgantown. He and his colleagues acknowledge more study of bryostatin is needed, but add it is reasonable to think the drug could prevent progression of AD associated with the buildup of certain plaques in the brain. The drug was developed to treat cancer. Bryostatin faces more study and testing before it might be used to treat AD. The U.S. Food and Drug Administration has already approved it for some cancer trials, which could speed the approval process, Alkon said.

For the study, mice were bred to carry human genes causing AD. Some were injected with bryostatin, a control group was not. Researchers found that bryostatin helped mice break down proteins involved in the development of amyloid plaques, protein deposits in the brain associated with AD. The study found lower levels of the precursors to these plaques in mice treated with the drug. AP 7/27/04 Proceedings of the National Academies of Science 7/27/04 vol 100, no 30,11141-11146

Donepezil Appears to Help Moderate to Severe AD Patients - Researchers analyzed data from the Moderate to Severe AD Study, a 219-patient study carried out in Australia, Canada, and France. Patients were randomly assigned to take either donepezil (Aricept) or a placebo for six months. Interviewers asked the patients’ caregivers about how well patients could perform basic daily activities like eating and taking a bath. Patients who took donepezil declined more slowly than patients on placebo. Patients on donepezil were especially likely to do better on initiation - for example, deciding to bathe without being reminded or deciding to use the bathroom. Patients on donepezil were also more likely to be engaged with others. Caregivers were also less likely to be stressed if the patient was taking donepezil. Based on some measures, AD patients on donepezil appear to live better, and the drug may reduce the stress on caregivers. By Helen Fields USNews.com 9/2/04 Geriatrics & Aging. May 2004, Vol. 7, No. 5, pp. 34–36

AD Hope in Old Drugs? - Old drugs used for decades to treat schizophrenia, stroke, breast cancer and other ailments, help to control a substance that regulates how calcium behaves in human cells. These drugs could be potent weapons against AD. Overabundant calcium is believed to be a key contributor to AD. If the new technique works, “it could give people a chance to have normal brain function longer,” the study’s co-author, Danton O’Day, a biology professor at the University of Toronto’s Mississauga campus, said in an interviewwith the Toronto Star 7/29/04. The theory developed by O’Day and U of T doctoral candidate Michael Myre begins with the idea that brain cells in AD patients get “leaky” and are flooded with an overabundance of calcium. It’s not yet understood why this happens, but it appears the process feeds on itself: the more calcium in the cells, the more is allowed in. And the results are devastating. Calcium can’t do anything by itself, O’Day said. But cells contain a substance called calmodulin, which normally activates protein enzymes in cells in a beneficial way. But when there’s too much calcium, calmodulin runs amok. It shuts down some proteins that should be active and over-stimulates others. “It’s like having the lights turn on when you’re trying to sleep, or the air conditioner coming on in the middle of winter,” O’Day said. The calmodulin reaction to calcium is believed to produce the characteristic development of AD: cell walls get covered in plaque and their interiors fill with fibrous material. They lose the ability to communicate with each other and eventually die. As more cells die, the brain loses its ability to function. By Peter Gorrie Feature Writer Toranto Star 7/30/04

Patients With AD Who Discontinue Reminyl (Galantamine) Treatment Seem to Experience Cognitive Decline - New data presented recently at the International Conference on AD suggest that patients with mild to moderate AD who continued treatment with Reminyl® for a six-week period maintained improvement in cognitive function, compared to patients who discontinued treatment and experienced a significant, rapid cognitive decline during the same period of time. Doctor’s Guide 8/23/04

Memantine Cost-effective for Severe AD - The cost of treating patients with moderately severe to severe AD with the drug memantine are more than offset by overall savings, European researchers report in the journal Clinical Drug Investigation. Memantine is marketed in the US by Forest Laboratories under the tradename Namenda. Using a mathematical simulation, Dr. Clement Francois, from Lundbeck SA, and colleagues estimated the cost implications of using memantine relative to no drug therapy over a 5-year-period in patients with moderate to severe AD in Finland. The data for the model were derived from a study of dementia among older adults in Finland and from a clinical trial conducted in the US. As anticipated, the initial cost of memantine therapy outweighed that of no therapy. But as the study period progressed, memantine was found to be cost-effective, largely because it helped patients remain at home rather than be sent to a hospital or nursing home. “Memantine therapy was associated with approximately 4 extra months of independence, 1 additional month of residence in the community, and a cost reduction relative to placebo of approximately 1700 euros per patient over 5 years,” the authors write. Reuters Health 8/20/04 Clinical Drug Investigation, July 2004

Speed up AD Trials, Researchers Say - Regulators, researchers and drug companies must work quickly to develop faster and less expensive trials for treatments to prevent and treat AD, scientists said July 2004 at the International Conference on AD in Philadelphia. Promising medications are in the works, but human trials are time-consuming and costly, and an avalanche of AD cases is expected as the baby boom generation ages, they told a conference. “We need to reduce the time it takes to do these studies, cut the costs involved, and find ways to conduct effective studies with fewer numbers of participants,” said Dr. Marcelle Morrison-Bogorad, an associate director at the National Institute on Aging. Reuters 7/19/04

Promising Drug Trials - An AD vaccine designed to stop the disease’s progressive destruction has shown promise in a trial of more than 300 patients, but the research was halted before the patients received a full course of treatment because some developed brain swelling. Patients who received the vaccine scored better on memory tests a year later than those who were not given the vaccine; there was no perceptible difference in the patients’ day-to-day functioning. In addition, an examination of the brains of four patients who died found a marked reduction in the plaque-like substance that typically fills space between brain cells in AD. “It’s very exciting,” said Dr. Sid Gilman, endowed professor of neurology at the University of Michigan who was involved in the study, sponsored by California-based Elan Corp. The findings were presented 7/21/04 at the International Conference on AD. The vaccine used in the trial has been abandoned. Elan scientists and others are pursuing other immunization strategies. “The changes are not dramatic but they are in the right direction,” said Dr. Sam Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University in Philadelphia. By Jamie Talan Staff Correspondent Newsday.com 7/22/04

Neramexane Fails to Find Statistical Significance in Trial for AD Treatment - Forest Laboratories Inc. announced 9/6/04 that in a preliminary analysis, data from the first Phase III study of the investigational AD treatment, neramexane, failed to achieve statistical significance. The six-month, double-blind, parallel-group Phase III study was designed to evaluate the safety and efficacy of combination therapy with neramexane and any of the three most widely prescribed acetylcholinesterase inhibitors (AChEI) compared to an AChEI alone in 415 outpatients with moderate to severe AD. Forest is currently enrolling moderate to severe AD patients in a second Phase II/III study examining neramexane as monotherapy compared to placebo and plans to continue the clinical development of the compound, the release said. Neramexane is a cyclohexane derivative belonging to a class of drugs called N-methyl-D-aspartate (NMDA)- receptor antagonists. Neramexane is believed to selectively block the effects associated with abnormal transmission of glutamate (a neurotransmitter that performs an integral role in the neural pathways associated with learning and memory) while allowing for the physiological transmission associated with normal cell functioning. Pharmabiz.com 9/6/04

Genes & Genetic Issues

Researchers Make Discovery That May Halt Progression of AD - In a finding that may cause a dramatic shift in the way scientists and researchers search for a therapy for AD, a team of researchers led by Jeff Johnson, an associate professor at the School of Pharmacy at the University of Wisconsin Madison , has discovered that increased expression of a protein called transthyretin in the brain appears to halt the progression of the disease. “If we can intervene in AD pathology by introducing molecules and drugs into the brain and increase transthyretin levels, we could slow the progression of the pathology,” says Johnson. “Even if patients have plaque formation in the brain, they still could have normal function.” Johnson’s research is based on the widely held amyloid hypothesis: When amyloid precursor protein (APP) is cut into pieces in the human brain, there are “good” cuts - proteins that help to protect neurons - and “bad” cuts, toxic beta-amyloid protein that, when present in large amounts, causes massive neural cell death, leading to cognitive function loss. In AD patients, “bad-cut” proteins significantly outnumber “good cut” proteins. The researchers analyzed the brains of the mice with plaque formation, and noticed the levels of a pair of specific proteins, transthyretin and IGF-2, increased dramatically. Since transthyretin had been shown in test tubes to bind to the toxic beta-amyloid protein, the researchers hypothesized that in the mice, the transthyretin was preventing the “bad cut” toxic beta-amlyoid protein from interacting with the neuronal cells, thereby preventing tangle formation and subsequent neuronal cell death. Further experimentation bore out their theory. The next question involves developing a reliable method to deliver transthyretin into the brain, or developing drugs that increase transthyretin expression in the brain to combat the neurotoxicity of beta-amyloid. By Aaron Conklin The University of Wisconsin Madison 9/2/04 The Journal of Neuroscience, Sept 1, 2004, 24(35):7707-7717

Drinking and Dementia: Is There a Link? - Drinking alcohol in middle age may increase the risk of late-life dementia in people who are genetically predisposed to develop, according to findings from a Scandinavian study. Researchers from Stockholm’s Karolinska Institute reported that infrequent drinkers have a twofold increase in the risk of dementia in old age among carriers of a gene that has been linked to AD. Gene carriers who frequently drink had a threefold increase in risk. But the findings also show a protective effect for infrequent drinkers who did not have the genetic risk factor. Low-risk teetotalers and frequent drinkers in the study were twice as likely to experience mild cognitive declines later in life as infrequent drinkers. The study included just more than 1,000 men and women followed for an average of 23 years, who were between the ages of 65 and 79 at follow-up. The researchers took blood samples to determine which study participants were carriers of the apolipoprotein E genotype. The genotype is an established risk factor for dementia in old age, and as many as one in four Americans are carriers, said researcher Miia Kivipelto, MD, PhD, to WebMD. The Karolinska researchers reported that dementia risk appeared to be directly related to drinking frequency among study participants who were carriers of the gene. “Our current data indicate that frequent alcohol drinking has harmful effects on the brain, and this may be more pronounced if there is genetic susceptibility,” the researchers wrote. “We therefore do not want to encourage people to drink more alcohol in the belief that they are protecting themselves against dementia.” By Salynn Boyles WebMD Medical News 9/2/04 BMJ (formerly the British Medical Journal) 2004;329:539 (4 Sept.)

Longevity Protein May Slow Many Neurodegenerative Disorders - A protein, Sir2, linked to increased lifespan in yeast and worms also can delay the degeneration of ailing nerve cell branches, according to researchers at Washington University School of Medicine in St. Louis. Scientists report their findings might open the door to new ways to treat a wide range of neurodegenerative disorders, including Parkinson’s disease, AD, amyotrophic lateral sclerosis (Lou Gehrig’s disease), various kinds of neuropathy, and multiple sclerosis. “It’s becoming clear that nerve cell death in these disorders is often preceded by the degeneration and loss of axons, the branches of the cells that carry signals to the synapse,” says senior investigator Jeffrey Milbrandt, M.D., professor of medicine and of pathology and immunology. “If this mechanism for delaying or preventing axonal degeneration after an injury proves to be something we can activate via genetic or pharmaceutical treatments, then we may be able to use it to delay or inhibit nerve cell death in neurodegenerative diseases.” Milbrandt and colleagues showed in mouse nerve cells that the protein SIRT1, which belongs to a family of proteins known as the Sir2 group, delays the breakdown of axons in nerve cells mechanically cut off from the cell body or exposed to a chemotherapeutic agent. “The next step is to find out what genes SIRT1 is turning on and off that protect axons when the nerve cell is injured,” Milbrandt says. “We’ll also be looking at whether gene therapy approaches that increase these protective effects can delay disease in mouse models of human neurodegenerative disorders. We’ve already heard from a number of colleagues who are eager to give these pathways a try.” PR 8/12/04 Science, vol 305, 5686, 1010-1013, 13 Aug 2004

Hopes Now Outpace Stem Cell Science - When Ron Reagan gave his speech on stem cell research before the Democratic National Convention on 7/27/04, medical researchers were taking careful note. It was just so important to them that he get the details right, that he make no mistakes on the science and that they glean any tricks they could on how to get their message about the importance of stem cell research across. But for all the promise, and for all the fervent hopes of patients and their families that cures from stem cells will come soon, researchers say many questions in basic science remain to be answered. Researchers have not yet cured any disease or even routinely turned embryo cells into specific adult cells. They got furthest in mice, where they converted mouse stem cells into brain cells like those lost in Parkinson’s and into blood cells. Dr. Ronald McKay, a stem cell researcher at the National Institute of Neurological Disorders and Stroke, counseled patience. “We are essentially getting cells to differentiate without the rest of the embryo,” Dr. McKay said. “That has to be controlled and it has to be controlled in the lab. It’s tricky stuff and it will take quite a while to figure out.” But, he said, to get to the next stage, when animals can routinely be cured of some diseases, like diabetes or Parkinson’s, “is likely going to take a new wave of technology or experiments.” By Gina Kolata NY Times 7/29/04

Caregivers

Caregivers Get No Emotional Relief from Institutionalizing Relatives with Dementia -

Caregivers who must make the difficult decision to place their relatives into institutionalized care get no relief from depression and anxiety and, in fact, suffer additional emotional trauma following their decision. Results from the four year study of 1,222 caregiver-patient pairs found that for the 180 caregivers who had to turn over care of their loved one to an institution, symptoms of depression and anxiety stayed as high as they were when they were in-home caregivers. “Caregivers who place their loved ones in an institution do not get the sense of relief or experience the closure observed among caregivers whose loved ones pass away,” said Dr. Richard Schulz at the University of Pittsburgh School of Medicine. “They continue to feel distressed because of the suffering and decline of their loved one as well as having to face new challenges such as frequent trips to the long-term care facility, reduced control over the care provided to their relative, and taking on responsibilities such as coordinating and monitoring care.” In addition, said Dr. Schulz, cognitive and functional declines are common in patients who go into long-term care, and caregivers often blame themselves for this decline and question their decision to institutionalize their loved one. “This study shows that we need to help caregivers who place their relatives. We need to treat their emotional distress, educate them about the nature of long-term care facilities and their impact on patient functioning, engage them in end of life planning, and prepare them for the eventual death of their loved one,” said Dr. Schulz. PR 8/24/04 Journal of the American Medical Association (JAMA) 2004;292:961-967

Testing

Doctors Say Commercial Scans for AD Questionable - The ability of doctors to scan the brain to look for early signs of has advanced dramatically in the past two years, but researchers say the technology is ripe for abuse. AD researchers said commercial firms have begun advertising brain scans to detect AD, a practice they said had little value for most people and may even been detrimental. In the past two years, positron emission tomography has developed to the point where it can detect the so-called plaques and tangles of proteins that accumulate in the brains of people with AD. There also have been advances in magnetic resonance imaging. Still, except for research applications and other limited uses, the technology has little value to the general public, according to several scientists who presented research here at the Ninth International Conference on AD and Related Disorders. “I have reservations about everybody jumping on the bandwagon,” said Shi-Jiang Li, a professor of biophysics at the Medical College of Wisconsin who is developing MRI scans to detect AD. “I think abuse is the right word.” PET and MRI scans can be expensive, ranging from $1,500 to $2,500. In addition, Weiner said, PET scans can needlessly expose people to radiation. He said the best way to diagnose AD is through a battery of cognitive tests. The Milwaukee Journal Sentinel 9/5/04

Prevention

AD Advance: Omega-3 Fatty Acid Benefits Mice - A diet that includes a key omega-3 fatty acid found in fish and canola oil prevents some memory loss in mice that develop a disease similar to AD. The finding is consistent with previous research suggesting that fish oil supplements might reduce the risk of AD in people. Other work has shown that the fatty acid, called docosahexaenoic acid (DHA), is essential to brain function and that AD patients have low concentrations of it in their blood. The early memory and learning problems that mark the disease occur because damaged brain cells fail to transmit messages consistently to each other across junctions called synapses. To assess what role DHA might have in maintaining this transmission, Greg M. Cole, a neuroscientist at the University of California, Los Angeles (UCLA) and his colleagues used old mice - 17 months on average - that were genetically engineered to develop waxy protein plaques in their brains, much as AD patients do. Some mice received food without DHA for 103 days and subsequently showed depleted stores of DHA in their brains. In contrast, mice getting chow supplemented with DHA had high brain concentrations of the fatty acid. Notably, these animals maintained good concentrations of two proteins that enable synapses to function, but DHA-deficient mice had insufficient concentrations of those substances. Commenting on the study, nutritionist Julie A. Conquer of the University of Guelph in Ontario says that these results show that DHA in the diet can affect the biochemistry of brain- signaling pathways. Cole and his team also tested memory in elderly mice that had received food with or without DHA for nearly 5 months. Those with DHA had better spacial memory than those without. Study coauthor Sally A. Frautschy, a neurobiologist at UCLA, said this memory is “like trying to remember where you parked your car. That’s memory you lose in AD.” Conquer says that research into omega-3 fatty acids in AD is now taking two tracks. Studies on the biological track, which include the new work by Cole and his colleagues, seek to clarify how the fatty acids affect brain function. The other research approach centers on monitoring the course of disease in newly diagnosed patients taking or not taking fatty acid supplements. Among the outstanding questions is the role of the waxy plaques, made of the short protein amyloid beta, in AD. Cole hypothesizes that an accumulation of the substance causes oxidative damage to DHA. By Nathan Seppa Science News Online 9/4/04 Neuron Vol 43,633-645, 2 Sept. 2004.

“Good” Cholesterol Protects Women Against Dementia - For women, maintaining high levels of “good” HDL cholesterol may be one of the most effective strategies for fending off AD, according to new research. Data from the ongoing Women’s Health Study indicate that women with the highest HDL levels -- ranging from 60 to 75 -- have half the risk of becoming mentally impaired as those with the lowest levels. The findings were reported 7/21/04 at the International Conference on AD. Lead investigator Elizabeth Devore, a graduate student at Harvard Medical School in Boston, said women with the highest LDL (“bad”) cholesterol levels had a slight increase in risk of AD, but “clearly HDL is the more important in determining a woman’s risk.” During the 1998-2000 evaluations, cognitive assessments were conducted on 4,081 subjects aged 65 or older. The odds of cognitive impairment declined with increasing levels of HDL. Even “subtle decrements in cognitive function strongly predict eventual development of AD,” Devore and her colleagues point out in their report. Their findings are “good news because we know how to modify HDL,” Devore said at a press conference. She noted that exercise, weight loss and moderate alcohol intake -- one to two drinks a day -- have all been shown to increase HDL levels. “But exercise is the most important element, even more important than diet.” By M. Mary Conroy Reuters Health 7/21/04

Iron Deficiency May Play Role in AD Researcher Says - Iron deficiency may play a role in AD. The finding could be a big step in understanding and ultimately delaying or preventing the disease. A shortage of a specific type of iron starves brain cells to death, says biochemist Hani Atamna of Children’s Hospital and Research Center. This discovery may be a key piece to the puzzle of how AD destroys brain cells and causes progressive dementia. It is very important to have enough iron in your system as you age, said Atamna. Normally, cells take iron into their internal power plants and use it to produce a different kind of iron known as heme. The heme is then sent to other parts of the cell that need it in order to function. Atamna found that heme can also bind to the proteins, effectively stopping them from becoming insoluble plaques, and then the heme flushes them out of the cell. But when too much heme is used up on the proteins, too little is left to power the cell. So the cell’s power plant responds by ratcheting up heme production to compensate for the shortage. But this is where a cell can get into trouble. The cellular power plant starts producing extra heme in order to both run the cell and clean out the proteins. The cell seems to over-react and pump out too much extra heme. This is dangerous because heme reacts with oxygen to produce molecules known as free radicals that damage the power plant and starve the cell to death. Atamna compared heme levels in the autopsied brains of people with AD to those without the disease. “We found that heme in AD brains was increased to about three times its level in the normal brains,” he said. Having enough iron on hand is vital. Because heme is needed to flush out the protein plaques that begin to form with age, a shortage of the iron needed to produce heme when those plaques first start showing up could lead to a plaque build-up. This in turn triggers the cells to start producing the extra heme that will eventually lead to their death. Though his research doesn’t prove an iron deficiency causes AD, Atamna believes it may be possible to slow down, or even delay the onset of the disease by starting out with a fatter brain bank account, full of iron and other important vitamins. By Betsy Mason Knight Ridder Newspapers 8/20/04 Proceedings of the National Academy of Science July 27, 2004 vol. 101, No. 30 pp 11153-11158

Obese Mid-lifers at Higher Risk of Dementia - People who are obese in middle age are twice as likely to develop dementia in later life as people who are not obese. But, if high cholesterol and hypertension are added to the equation, the risk of dementia increases six times, according to research from Sweden and Finland. The findings are from a long-term epidemiologic investigation of the interactions of lifestyle, genetic factors and vascular health on cognitive health. The first cohort for the study was enrolled in 1972. The findings were presented at the Ninth International Conference on AD by Dr. Miia Kivipelto from the Karolinska Institute in Stockholm. The study showed that BMI (body mass index) indicator of increased risk for dementia in later life. Obesity is related to several of the risk factors for dementia and AD, especially vascular disease factors. “The more vascular risk factors, the greater the risk for dementia. Therefore, elimination of even one risk factor could substantially decrease this risk,”she said. And, reducing BMI can affect vascular risk factors. The study adds fodder for the push to encourage patients to try to attain or maintain a normal body weight and get treatment for vascular disease. After all, losing weight could “increase the chances of eluding dementia and AD she said. By Pippa Wysong The Medical Post 8/10/04

AD Linked to Lowbrow Jobs - A mentally stimulating career may help to reduce the risk of AD, research suggests. According to a study carried out in the United States, those who develop the debilitating form of dementia are more likely to have had jobs that do not tax the brain.

The discovery lends weight to the “use it or lose it” theory, says Kathleen Smyth of Case Western Reserve University in Cleveland, Ohio, who led the research. Experts have previously suggested that keeping the mind active, through reading or crossword puzzles, can help to stave off dementia in old age. The researchers are not sure exactly how the effect works. It may be more likely that the brain really does benefit from sustained activity, rather than a lifetime spent working in a factory. Smyth suggests that people who stimulate their minds might build up a reserve of nerve cells in the brain. This would allow them to remain clear-headed even as their brains became clogged with the clots of protein that characterize AD. By Michael Hopkin Nature.com 8/10/04 Neurology, 63. 498-505 (2004)

Book Offers Tips on Improving Memory as We Age - A new book “Memory Fitness: A Guide for Successful Aging,” co-authored by Mark A. McDaniel, a memory researcher at Washington University in St. Louis and Gilles O. Einstein, professor of psychology at Furman University. is one-stop shopping for all the questions we have about memory and how serious our lapses might be as we grow older. McDaniel says his book relies on many rigorous academic studies but is written for the lay person. “Our mission is to give the general public a good idea of what they can reasonably expect from their memory capabilities as they age,” says McDaniel, “It also outlines some reasonable expectations about things people can do to perhaps increase their memory performances.” “As we age,” McDaniel explains, “almost every part of neuron function you can think of starts to deteriorate a bit.” In other words, neurons - the nerve cells that make up our brains - naturally lose some functionality throughout a lifetime. This is partially responsible for the “senior moments” and other lapses that people commonly encounter, which McDaniel stresses are normal - usually. “Older adults who participate in our studies,” says McDaniel, “tell us that the information they want us to convey [about memory] is in different sources - it’s not integrated into one source. What we’ve tried to do with this book is to integrate basic memory processes and how they change with age, cognitive strategies to improve memory, lifestyle changes like diet, nutrition and exercise, and basic information about AD including ways to recognize and cope with the disease.” The authors offer strategies to stay sharp, despite those normal losses in memory function that come with age. Some of these are surprisingly simple.

“Take courses, teach somebody something, discuss movies or books; do anything that makes you struggle and problem-solve through significant cognitive effort,” McDaniel suggests. “There are studies that show an association between challenging daily mental activity and memory maintenance as well as less dramatic loss of memory function. It appears that by challenging yourself, you can better preserve your memory capacities.” Additionally, regular exercise may help. “I’m increasingly convinced,”says McDaniel, “that strength training is an important part of an exercise program that one might undertake to improve brain health.” Medical New Today 8/14/04

Dietary Niacin May Protect Against the Development of AD - Dietary niacin (vitamin B3 ) may protect against the development of AD and the cognitive decline associated with ageing in older people. Rich sources of niacin include lean meat, fish, legumes, nuts, dairy products, enriched grains and cereals, and coffee and tea. The researchers base their findings on almost 4000 people aged 65 and older, who had no AD. At three years, a random sample of 815 people, who had not initially had AD, were checked for clinical changes and their dietary niacin intake assessed by means of food frequency questionnaires. Among this smaller group, 131 people were diagnosed with AD. After adjusting the results for age, gender, race, educational levels, and the ApoE gene - all important risk factors for the disease - those with the lowest food intake of niacin (an average of 12.6 mg/day) were 80% more likely to be diagnosed with AD than those with the highest intake (22.4 mg/day). An analysis of the larger group showed that the rate of cognitive decline among those with the highest niacin intake was almost half (44%) that of those with the lowest intake. Niacin has been prescribed to older people to prevent confusional states, and severe deficiency causes pellagra, a condition characterised by dementia, diarrhoea, and dermatitis, but its role in AD has not been thoroughly explored, say the authors. Previous research has indicated that niacin has an important role in DNA synthesis and repair, neural cell signalling, and acts as a potent antioxidant in brain cells, they say. Medical Research News 7/15/04 Journal of Neurology Neurosurgery and Psychiatry 2004;75:1093-1099

Other Items

Risk of Dementia Increases after Stroke - The likelihood of developing dementia is high after stroke, according to the results of a study published in the medical journal Neurology. The study also found that the characteristics of post- stroke dementia appear to shift. In the first years after stroke it seems to be an AD-type disease, then changes to a vascular dementia type in later years. Dr. Marta Altieri, of the University of Rome “La Sapienza,” in Italy, and colleagues followed non-demented 191patients from 6 months after stroke onset for 4 years. The subjects underwent annual neuroimaging and neuropsychological tests. Forty-one patients (21.5 percent) had developed dementia by the end of the follow-up period. “Among the 41 patients who became demented, 26 (63.4 percent) met the criteria for probable vascular dementia and 15 (36.6 percent) for possible AD,” Altieri and colleagues write. The study “confirms data showing that dementia is a frequent consequence of stroke,” the authors conclude. Reuters Health 7/12/04 Neurology 2004;62: 2193-2197

Decreasing Toxins in Brains of AD Patients Keep Cognitive Deficits at Bay - The ever-slowing capacity to clear the build-up of such toxins as isoprostanes and misfolded proteins that accumulate in the brains of AD patients causes the death of cells involved in memory and language. Domenico Pratico, MD, Associate Professor of Pharmacology at the University of Pennsylvania School of Medicine, and colleagues have shown in a preliminary study that reducing the levels of isoprostanes, which specifically reflect oxidative damage in the brain, by draining cerebral spinal fluid (CSF) can stave off future reductions in cognitive abilities. As measured by a paper-and-pencil cognitive test, the researchers found that scores of the eight patients who had the specially designed shunt continuously operating for one year stayed stable. However, the scores of patients who did not get the shunt declined by 20 percent after 12 months. “What’s interesting is that the patients without the shunt didn’t stop taking their regular AD medication, such as anti-cholinesterase,” says Pratico. Over 12 months, the isoprostanes were reduced by about 50 percent compared to AD patients taking standard anti-AD oral medications alone. “We were very happy to see this amount of reduction,” says Pratico. Additionally, the normal components of CSF like glucose and immunoglobulins did not change after the shunt was placed in patients. The shunt has a selective capacity to filter out toxins of a specific molecular weight and size, in this case isoprostanes. Tthe microns-wide shunt, or catheter, is placed subcutaneously in a space at the base of the cerebellum. It runs under the skin to the peritoneum, a space in the belly where body fluids accumulate before flowing to the kidney to be filtered and eventually eliminated in the urine. The shunt is put in once, drains continuously, and is cleaned out periodically by a neurologist. PR 8/23/04 The Journal of Alzheimer's Disease vol 6, no 4, 385-389

Is Help on the Horizon for AD? - Dr. Rudy Tanzi professor of neurology at Massachusetts General Hospital believes the day is closer than ever for a treatment for those suffering from AD. “Usually five to 10 years is just a way to say I have no idea when it will happen. But I truly believe if you calculate it now, it’s five to 10 years.” While aging baby boomers will contribute largely to the rise in AD, other factors could help fuel the increase. One such factor appears to be diabetes, Tanzi said. His lab demonstrated a genetic link between the two disorders, discovering in experiments with mice that if the insulin-degrading enzyme gene is removed, “you get AD-type features in the brain and Type II diabetes,” he said. That research also revealed a link between that gene and susceptibility to AD. Studies have also linked obesity, high blood pressure and high cholesterol to increased risk for AD, where the sticky amyloid plaque collects in the brain. In one study, middle-aged adults with high cholesterol were at least three times more likely to develop dementia as early as the 60s. Because of the possible role cholesterol plays, some have suggested cholesterol-lowering drugs as a possible solution to AD. Other drugs are being developed specifically for AD, most of them aimed at slowing the breakdown of a neurotransmitter that’s important for the formation of memories. These drugs have helped stabilize memory and thinking skills in some patients, but none stop or reverse AD. Tanzi’s wife, Dr. Dora Kovacs, has done tests involving an enzyme inhibitor that wiped out more than 90 percent of the amyloid plaque in mice. He’s excited by the research of one of his companies, Prana Biotechnology, involving copper and zinc, metals which help collect the plaque. “You can dissolve and clear away amyloid by stripping copper and zinc away,” he said. In experiments with mice, drugs got rid of plaque in as few as nine weeks. Prana has now started clinical trials with AD patients to test those drugs. Tanzi’s other company, Neurogenetics Inc., is also working on AD research, developing therapies to safely curb the production of amyloid. Finding a solution to AD involves paying attention to how the body works or doesn’t work, he said. “You just follow the genetics, and it will tell you what you need to fix.” By Jerry Mitchell The Clarion-Ledger 8/26/04

AD Risk Increases after Coronary Bypass - Mental impairment is a known risk following coronary bypass surgery, and now researchers have found that the procedure may hasten the emergence of AD. The results of a large study indicate that the risk of developing AD within five years is 70 percent higher following coronary artery bypass grafting (CABG) than after percutaneous coronary angioplasty (PCTA). Both procedures are used to deal with restore blood flow to the heart when coronary arteries become blocked. The researchers compared outcomes of over 5000 coronary bypass patients and nearly 4000 angioplasty patients treated at the Hines VA Hospital in Illinois. All patients were 55 or older at the start of the study and had no dementia. They were followed for five years after their procedures. “Seventy-eight of the CABG patients and 41 of the PTCA patients were diagnosed with AD during the follow-up,” Dr. Benjamin Wolozin, professor of pharmacology at Boston University School of Medicine, reported at the International Conference on AD and Related Disorders. While this translates to a higher risk for AD after coronary bypass than after angioplasty, Wolozin cautioned that the results should not “affect the decision to treat a patient with CABG, which is an excellent, life-saving surgery.” In an interview with Reuters Health, Dr. Martin Bednar, the lead author of the study, pointed out that the recognized mental deficits that can occur after coronary bypass are diagnosed soon after surgery. “This is the first study to report on risk,” he said. Wolozin said he thinks the increased risk of AD is a result of stress caused by surgery that triggers an increase in stress hormones, which “may trigger a cascade of events that reduce the oxygen to the brain.” While not advising against coronary bypass, Wolozin said that some CABG patients may benefit from approaches that could reduce stress, including possibly increasing the supply of oxygen and glucose to the brain during surgery. Reuters Health 7/21/04

Researchers Study AD-Race Link - Minorities may be harder hit by AD than whites. A study presented to a conference on AD shows that Hispanics begin to show symptoms of AD at younger ages than whites, while another study showed middle-aged blacks are more likely to suffer from the disease than whites of the same age. “Studies like this should serve as a wake-up call to Congress and the nation,” said James Jackson, a member of the Alzheimer’s Association Medical & Scientific Advisory Council. “Minorities face disproportionate burdens of many diseases, including some that may contribute to AD,” Jackson added in a statement. “As minority populations get older, they will see a dramatic rise in their risk of AD. This will overwhelm their families and communities unless we take action now.” Several studies presented at the Philadelphia conference show that obesity, high cholesterol and high blood pressure can all raise the risk of AD. Many minority groups suffer from a higher rate of these cardiovascular risk factors. Reuters 7/21/04

Parkinson’s-AD Link Seen Unlikely - It has been thought that there might be a genetic link between AD and Parkinson’s disease, but that seems not to be the case. Researchers have found that the odds of developing AD is not increased among relatives of people who have Parkinson’s disease, compared with relatives of unaffected “control” subjects. It seems unlikely therefore that there are “major shared genetic contributions” to the development of these two diseases according to a report in the July issue of the Archives of Neurology by Dr. Karen Marder from Columbia University, New York, and associates. “If there were a major shared genetic influence on Parkinson’s disease and AD, we would have expected both an increased risk of Parkinson’s disease in AD families and an increased risk of ADin Parkinson’s disease families,” Marder told Reuters Health. “While clearly there is some overlap in some families in which AD and Parkinson’s disease co-exist, there is probably not a huge overlap,” Marder concluded. Reuters Health 8/6/04 Archives of Neurology, 2004;61:1033-1039

A Study on Yeast Proteins Provides Some Answers about Amyloid Plaques in AD - One of the distinguishing features of AD is the globs of protein, known as amyloid plaques, that form in the brain. Amyloid fibers are very strong, and there is no known way to break them down. But scientists at the Whitehead Institute for Biomedical Research have found a protein that disassembles amyloids in yeast. In yeast Sup35 is a yeast protein that forms amyloid fibers and Hsp104 is another yeast protein. The scientists did many experiments with the isolated proteins - particularly, adding small and large amounts of Hsp104 to Sup35 and seeing whether Sup35 would still form amyloid fibers. They found that while small amounts of Hsp104 helped Sup35 turn into amyloids, large amounts stopped the amyloids from forming. And adding Hsp104 could actually disassemble amyloid fibers - if left long enough, fibers could be “completely obliterated,” the authors write. By Helen Fields USNews.com 9/1/04 Science June 18, 2004, Vol. 304, No. 5678, pp. 1793–1797

AD16\adnews0904f.wpd