New Findings About Brain Proteins Suggest Possible Way To Fight Alzheimer's

The action of a small protein that is a major villain in Alzheimer's disease can be counterbalanced with another brain protein, researchers at UT Southwestern Medical Center have found in an animal study.The findings, available online in the journal Proceedings of the National Academy of Sciences, suggest a promising new tactic against the devastating illness, the researchers said.

The harmful protein, called beta-amyloid, is found in the brain and, when functioning properly, suppresses nerve activity involved with memory and learning. Its normal function can be likened to a red traffic light, restraining nerve cells from getting overexcited when they receive stimulating signals from neighboring cells. People with Alzheimer's disease, however, accumulate too much beta-amyloid – the traffic light gets stuck on "red" and nerve cells become less responsive.

Another brain protein, called Reelin, acts as a "green light," stimulating nerve cells to respond more strongly to their neighbors' signals.

The new study shows that applying Reelin directly to brain slices from mice prevents excess beta-amyloid from completely silencing nerves.

"If we can identify a mechanism to keep the nerve cells functioning strongly, that might provide a way to fight Alzheimer's disease," said Dr. Joachim Herz, professor of molecular genetics and neuroscience at UT Southwestern and the study's senior author.

In the study, the researchers recorded electrical currents in the mouse hippocampus, an area of the brain associated with learning and memory. From their experiments they determined that Reelin and beta-amyloid interact with the same protein complex, called an NMDA receptor, which plays an important role in coordinating chemical signals between adjacent nerve cells.

They found that Reelin activates and strengthens the response of the NMDA receptor. In the presence of too much beta-amyloid, the receptor migrates into the cell, reducing the cell's sensitivity to incoming signals. By contrast, in strong concentrations of Reelin, the receptor remains active and the cell has the green light to continue receiving normally.

Dr. Herz said the study is especially important because this mechanism involves another protein involved in Alzheimer's called ApoE4, which is the primary risk factor for the most frequent late-onset form of the disease. The receptor that binds to ApeE molecules also binds to Reelin, and is part of the red-light/green-light complex that controls the sensitivity of the NMDA receptors.

"These results imply that Reelin, ApoE and beta-amyloid converge on the same molecular mechanism, which is critical in the Alzheimer's disease process, and Reelin may be a common factor to fight both beta-amyloid and mutated ApoE," Dr. Herz said. "This study establishes a rationale that ApoE receptors have an action that can keep the Alzheimer's disease process at bay by preventing damage in the first place."

The researchers are currently studying the role of ApoE4 in this mechanism. Mimicking or preserving normal Reelin function to stimulate the ApoE receptors might provide a path to stave off the disease, Dr. Herz said.

Other UT Southwestern authors included lead author Dr. Murat Durakoglugil, assistant instructor of molecular genetics; graduate student Ying Chen; Dr. Charles White, professor of pathology; and Dr. Ege Kavalali, associate professor of neuroscience.

The study was funded by the National Institutes of Health, the American Health Assistance Foundation, the Perot Family Foundation and the Humboldt Foundation.

How To Boost Value Of Alzheimer's-fighting Compounds

The polyphenols found in red wine are thought to help prevent Alzheimer's disease, and new research from Purdue University and Mount Sinai School of Medicine has shown that some of those compounds in fact reach the brain.Mario Ferruzzi, a Purdue associate professor of food science; Connie Weaver, Purdue's head of foods and nutrition; and Elsa Janle, a Purdue associate professor of foods and nutrition, found that the amount of polyphenols from grapeseed extract that can reach a rat's brain is as much as 200 percent higher on the 10th consecutive day of feeding as compared to the first. Many previous experiments, in which absorption was measured after single or sporadic doses, often found very little, if any, of the bioactive polyphenols reaching brain tissues. However, more chronic exposure appears to improve absorption.

"This shows that reasonable and chronic consumption of these products may be the way to go, rather than single, high doses, similar to drugs," said Ferruzzi, who collaborated on the research with Mount Sinai's Dr. Giulio Pasinetti. "It's like eating an apple a day, not a case of apples over two days every month."

A paper detailing the findings was published in the early online version of the September issue of the Journal of Alzheimer's Disease.

Polyphenols, compounds found in the skins and seeds of grapes, are thought to prevent the formation of beta-amyloid protein, which creates the plaque in the brain that causes Alzheimer's disease. Alzheimer's is a progressive brain disease that destroys memory and cognitive skills and affects as many as 4.5 million Americans, according to the National Institute on Aging.

Pasinetti, the Aidekman Family Professor in Neurology and director of the Center of Excellence for Novel Approaches to Neurotherapeutics, said discovering how polyphenols are absorbed and distributed to the brain can impact researchers' understanding of the amount of grape products or red wine a person would need to consume to most effectively combat Alzheimer's disease.

"The most important thing is that when we follow the repetitive administration of this compound, we were able to observe the transfer of the compound to the brain," Pasinetti said. "This may help us figure out the proper concentration necessary to get these chemicals to the brain."

Ferruzzi said the study dealt with polyphenols, but also could be important for determining proper doses of other compounds or drugs for patients. Testing of a pharmaceutical, for example, could show that the drug is too potent when given repetitively; whereas that might not be apparent if the drug is administered on non-consecutive days or weeks.

"It could become important in terms of side effects," Ferruzzi said. "You could be overdosing because the body is adapting and absorbing or metabolizing these compounds differently over time."

Pasinetti is the principal investigator for the Center of Excellence for Research and Complementary and Alternative Medicine in Alzheimer's Disease grant from the National Institutes of Health that funded the work. Ferruzzi said further studies will focus on the mechanisms that control absorption of compounds during chronic consumption.

Fish Really Is 'Brain Food': Vitamin D May Lessen Age-related Cognitive Decline

Eating fish – long considered ‘brain food’ – may really be good for the old grey matter, as is a healthy dose of sunshine, new research suggests.University of Manchester scientists in collaboration with colleagues from other European centres have shown that higher levels of vitamin D – primarily synthesised in the skin following sun exposure but also found in certain foods such as oily fish – are associated with improved cognitive function in middle-aged and older men.

The study, published in the Journal of Neurology, Neurosurgery and Psychiatry, compared the cognitive performance of more than 3,000 men aged 40 to 79 years at eight test centres across Europe.

The researchers found that men with higher levels of vitamin D performed consistently better in a simple and sensitive neuropsychological test that assesses an individual’s attention and speed of information processing.

“Previous studies exploring the relationship between vitamin D and cognitive performance in adults have produced inconsistent findings but we observed a significant, independent association between a slower information processing speed and lower levels of vitamin D,” said lead author Dr David Lee, in Manchester’s School of Translational Medicine.

“The main strengths of our study are that it is based on a large population sample and took into account potential interfering factors, such as depression, season and levels of physical activity.

“Interestingly, the association between increased vitamin D and faster information processing was more significant in men aged over 60 years, although the biological reasons for this remain unclear.”

“The positive effects vitamin D appears to have on the brain need to be explored further but certainly raise questions about its potential benefit for minimising ageing-related declines in cognitive performance.”

Gene Key To Alzheimer's-like Reversal Identified: Success In Restoring Memories In Mice Could Lead To Human Treatments

A team led by researchers at MIT's Picower Institute for Learning and Memory has now pinpointed the exact gene responsible for a 2007 breakthrough in which mice with symptoms of Alzheimer's disease regained long-term memories and the ability to learn.In the latest development, reported in the May 7 issue of Nature, Li-Huei Tsai, Picower Professor of Neuroscience, and colleagues found that drugs that work on the gene HDAC2 reverse the effects of Alzheimer's and boost cognitive function in mice.

"This gene and its protein are promising targets for treating memory impairment," Tsai said. "HDAC2 regulates the expression of a plethora of genes implicated in plasticity — the brain's ability to change in response to experience — and memory formation.

"It brings about long-lasting changes in how other genes are expressed, which is probably necessary to increase numbers of synapses and restructure neural circuits, thereby enhancing memory," she said.

The researchers treated mice with Alzheimer's-like symptoms using histone deacetylase (HDAC) inhibitors. HDACs are a family of 11 enzymes that seem to act as master regulators of gene expression. Drugs that inhibit HDACs are in experimental stages and are not available by prescription for use for Alzheimer's.

"Harnessing the therapeutic potential of HDAC inhibitors requires knowledge of the specific HDAC family member or members linked to cognitive enhancement," Tsai said. "We have now identified HDAC2 as the most likely target of the HDAC inhibitors that facilitate synaptic plasticity and memory formation.

"This will help elucidate the mechanisms by which chromatin remodeling regulates memory," she said. It also will shed light on the role of epigenetic regulation, through which gene expression is indirectly influenced, in physiological and pathological conditions in the central nervous system.

"Furthermore, this finding will lead to the development of more selective HDAC inhibitors for memory enhancement," she said. "This is exciting because more potent and safe drugs can be developed to treat Alzheimer's and other cognition diseases by targeting this HDAC specifically," said Tsai, who is also a Howard Hughes Medical Institute investigator. Several HDAC inhibitors are currently in clinical trials as novel anticancer agents and may enter the pipeline for other diseases in the coming two to four years. Researchers have had promising results with HDAC inhibitors in mouse models of Huntington's disease.

Remodeling structures

Proteins called histones act as spools around which DNA winds, forming a structure in the cell nucleus known as chromatin. Histones are modified in various ways, including through a process called acetylation, which in turn modifies chromatin shape and structure. (Inhibiting deacetylation with HDAC inhibitors leads to increased acetylation.)

Certain HDAC inhibitors open up chromatin. This allows transcription and expression of genes in what had been a too tightly packaged chromatin structure in which certain genes do not get transcribed.

There has been exponential growth in HDAC research over the past decade. HDAC inhibitors are currently being tested in preclinical studies to treat Huntington's disease. Some HDAC inhibitors are on the market to treat certain forms of cancer. They may help chemotherapy drugs better reach their targets by opening up chromatin and exposing DNA. "To our knowledge, HDAC inhibitors have not been used to treat Alzheimer's disease or dementia," Tsai said. "But now that we know that inhibiting HDAC2 has the potential to boost synaptic plasticity, synapse formation and memory formation, in the next step, we will develop new HDAC2-selective inhibitors and test their function for human diseases associated with memory impairment to treat neurodegenerative diseases."

The researchers conducted learning and memory tasks using transgenic mice that were induced to lose a significant number of brain cells. Following Alzheimer's-like brain atrophy, the mice acted as though they did not remember tasks they had previously learned.

But after taking HDAC inhibitors, the mice regained their long-term memories and ability to learn new tasks. In addition, mice genetically engineered to produce no HDAC2 at all exhibited enhanced memory formation.

The fact that long-term memories can be recovered by elevated histone acetylation supports the idea that apparent memory "loss" is really a reflection of inaccessible memories, Tsai said. "These findings are in line with a phenomenon known as 'fluctuating memories,' in which demented patients experience temporary periods of apparent clarity," she said.

In addition to Tsai, co-authors are Picower postdoctoral associate Ji-Song Guan; and colleagues from Massachusetts General Hospital; Harvard Medical School; the Whitehead Institute for Biomedical Research; MIT's Department of Biology; the Dana Farber Cancer Institute; and the Netherlands Cancer Institute.

This work is supported by the National Institute for Neurological Disorders and Stroke, the Stanley Center for Psychiatric research at the Broad Institute of Harvard and MIT; the NARSAD, a mental health foundation, the National Cancer Institute, the Damon-Runyon Cancer Research Foundation; the Dutch Cancer Society; the National Institutes of Health; and the Robert A. and Renee E. Belfer Institute for Applied Cancer Science.

Soybean Product Fights Abnormal Protein Involved In Alzheimer’s Disease

A vegan food renowned in Asia for its ability to protect against heart attacks also shows a powerful ability in lab experiments to prevent formation of the clumps of tangled protein involved in Alzheimer’s disease, scientists in Taiwan are reporting. Rita P. Y. Chen and colleagues point out that people in Asia have been eating natto — a fermented food made from boiled soybeans —for more than 1,000 years. Natto contains an enzyme, nattokinase, that has effects similar to clot-busting drugs used in heart disease.Nattokinase is sold a dietary supplement to improve the body’s circulatory system.

The scientists term this the first study on whether nattokinase also can dissolve amyloids. Those tangled proteins are involved in Alzheimer’s disease and several other health problems.

In the study, the nattokinase degraded several kinds of amyloid fibrils, suggesting its possible use in the treatment of amyloid-related diseases. “Moreover, since natto has been ingested by humans for a long time, it would be worthwhile to carry out an epidemiological study on the rate of occurrence of various amyloid-related diseases in a population regularly consuming natto,” the scientists say.

Mediterranean Diet Associated With Lower Risk Of Cognitive Impairment

Eating a Mediterranean diet appears to be associated with less risk of mild cognitive impairment—a stage between normal aging and dementia—or of transitioning from mild cognitive impairment into Alzheimer's disease, according to a report in the February issue of Archives of Neurology, one of the JAMA/Archives journals."Among behavioral traits, diet may play an important role in the cause and prevention of Alzheimer's disease," the authors write as background information in the article. Previous studies have shown a lower risk for Alzheimer's disease among those who eat a Mediterranean diet, characterized by high intakes of fish, vegetables, legumes, fruits, cereals and unsaturated fatty acids, low intakes of dairy products, meat and saturated fats and moderate alcohol consumption.

Nikolaos Scarmeas, M.D., and colleagues at Columbia University Medical Center, New York, calculated a score for adherence to the Mediterranean diet among 1,393 individuals with no cognitive problems and 482 patients with mild cognitive impairment. Participants were originally examined, interviewed, screened for cognitive impairments and asked to complete a food frequency questionnaire between 1992 and 1999.

Over an average of 4.5 years of follow-up, 275 of the 1,393 who did not have mild cognitive impairment developed the condition. Compared with the one-third who had the lowest scores for Mediterranean diet adherence, the one-third with the highest scores for Mediterranean diet adherence had a 28 percent lower risk of developing mild cognitive impairment and the one-third in the middle group for Mediterranean diet adherence had a 17 percent lower risk.

Among the 482 with mild cognitive impairment at the beginning of the study, 106 developed Alzheimer's disease over an average 4.3 years of follow-up. Adhering to the Mediterranean diet also was associated with a lower risk for this transition. The one-third of participants with the highest scores for Mediterranean diet adherence had 48 percent less risk and those in the middle one-third of Mediterranean diet adherence had 45 percent less risk than the one-third with the lowest scores.

The Mediterranean diet may improve cholesterol levels, blood sugar levels and blood vessel health overall, or reduce inflammation, all of which have been associated with mild cognitive impairment. Individual food components of the diet also may have an influence on cognitive risk. "For example, potentially beneficial effects for mild cognitive impairment or mild cognitive impairment conversion to Alzheimer's disease have been reported for alcohol, fish, polyunsaturated fatty acids (also for age-related cognitive decline) and lower levels of saturated fatty acids," they write.

Additional studies are needed to confirm the role of this or other dietary factors in the development of cognitive impairment and Alzheimer's disease, they conclude.

This work was supported by grants from the National Institute on Aging.

Genetic Change Prevents Cell Death In Mouse Model Of Parkinson's Disease

By shifting a normal protective mechanism into overdrive, a University of Wisconsin-Madison scientist has completely shielded mice from a toxic chemical that would otherwise cause Parkinson's disease.Parkinson's disease is a disabling and sometimes fatal disease that afflicts 1.5 million Americans, with about 60,000 new cases annually. Its major symptoms, including tremors and sluggish movement, have been traced to death of small numbers of nerve cells in the substantia nigra, a brain region that helps regulate movement.

Adding extra copies of a gene that makes a normal, protective protein neutralized a toxic chemical that would normally devastate the substantia nigra. "This complete abolition of toxicity was far greater than we expected," says Jeffrey Johnson, a UW-Madison professor of pharmacy. "It was striking. We thought we would see a 20 or 30 or 40 percent reduction in cell death."

The protective mechanism is initiated by a protein called Nrf-2, which is present in people and in mice, says Johnson. Nrf-2 (transcription factor NF-E2-related factor) is made by astrocytes, brain cells that play a supportive role to the neurons, which are the cells that actually carry nerve signals.

In recent years, researchers looking at a range of neurodegenerative diseases, including Alzheimer's and Lou Gehrig's diseases as well as Parkinson's, have focused on the astrocytes in their quest to help the brain protect itself from stressful conditions that are deadly to neurons. "Astrocytes way outnumber neurons and are found throughout the central nervous system," says Johnson. "Neurons have always gotten the Academy Awards, but astrocyte dysfunction is becoming a central theme in neurodegenerative disease. If we can figure out how to fix a sick astrocyte, or even prevent it from getting sick, that could offer profound protection against almost all neurodegenerative diseases."

Because neurons are impossible to replace, the present research focus in neurodegenerative disease is on preventing their death in the first place. Parkinson's disease can be treated for a time by replacing dopamine, the brain chemical made by the substantia nigra, but the treatment loses its efficacy over time.

In a study funded by the National Institute of Environmental Health Sciences and published in today's Proceedings of the National Academy of Sciences, Johnson and UW-Madison colleagues Pei-Chun Chen, Marcelo Vargas and Delinda Johnson studied mice with extra Nrf-2 genes. The astrocytes in these mice produced about twice the normal level of Nrf-2 protein.

The researchers then dosed the mice with MPTP, a chemical that kills neurons in the substantia nigra and has become the major mechanism for studying Parkinson's disease in mice. The toxicity of MPTP was discovered in 1982, when young drug users in California developed the classic symptoms of Parkinson's disease, a disease that usually strikes those over age 60. Researchers found that the synthetic heroin these people had used was contaminated with MPTP, and further studies showed that MPTP is highly toxic to nerve cells in the substantia nigra.

When astrocytes make Nrf-2, the protein attaches to their DNA, kick-starting activity in hundreds of genes that release chemicals that can protect nearby neurons from oxidation – a series of chemical reactions that can injure or kill cells. "The astrocytes are also probably sucking up the bad stuff, thereby reducing the oxidative environment and stress on the neurons," says Johnson, adding that his laboratory is trying to identify those specific protective chemicals.

Nobody can predict when a manipulation of Nrf-2 could reach clinical trials, which Johnson says are at the very least two years in the future. While these experiments altered the mouse cells with genetic engineering, human trials would probably use drugs to boost Nrf-2 production in astrocytes. Several labs, including Johnson's, are already searching for candidate drugs.

The stakes are high, Johnson says, because Nrf-2 also protects brain cells in models of such fatal brain diseases as Alzheimer's, ALS, and Huntington's disease.

Normally, neurons die in these neurodegenerative diseases to "commit suicide" through a process called programmed cell death. "Nrf-2 seems to rebalance the system," Johnson says, "in favor of what we call programmed cell life."

Alzheimer's Prevented And Reversed With Natural Protein In Animal Models

Memory loss, cognitive impairment, brain cell degeneration and cell death were prevented or reversed in several animal models after treatment with a naturally occurring protein called brain-derived neurotrophic factor (BDNF). The study by a University of California, San Diego-led team – published in the February 8, 2009 issue of Nature Medicine – shows that BDNF treatment can potentially provide long-lasting protection by slowing, or even stopping the progression of Alzheimer's disease in animal models.

"The effects of BDNF were potent," said Mark Tuszynski, MD, PhD, professor of neurosciences at the UC San Diego School of Medicine and neurologist at the Veterans Affairs San Diego Health System. "When we administered BDNF to memory circuits in the brain, we directly stimulated their activity and prevented cell death from the underlying disease."

BDNF is normally produced throughout life in the entorhinal cortex, a portion of the brain that supports memory. Its production decreases in the presence of Alzheimer's disease. For these experiments, the researchers injected the BDNF gene or protein in a series of cell culture and animal models, including transgenic mouse models of Alzheimer's disease; aged rats; rats with induced damage to the entorhinal cortex; aged rhesus monkeys, and monkeys with entorhinal cortex damage.

In each case, when compared with control groups not treated with BDNF, the treated animals demonstrated significant improvement in the performance of a variety of learning and memory tests. Notably, the brains of the treated animals also exhibited restored BDNF gene expression, enhanced cell size, improved cell signaling, and activation of function in neurons that would otherwise have degenerated, compared to untreated animals. These benefits extended to the degenerating hippocampus where short-term memory is processed, one of the first regions of the brain to suffer damage in Alzheimer's disease.

The demonstration of the effectiveness and safety of BDNF administration in animals provides "a rationale for exploring clinical translation" to humans, the team concludes, suggesting that the protective and restorative effects of BDNF on damaged neurons and neuronal signaling may offer a new approach to treating Alzheimer's disease.

This work builds on previous studies by Tuszynski and others, demonstrating the therapeutic affects of nerve growth factor (NGF) administered to patients with Alzheimer's disease. In 2001, Tuszynski and his team at UC San Diego Medical Center performed the first surgical implants of NGF genes into the brains of Alzheimer's patients, with follow-up results showing these patients experienced a possible slowing in cognitive decline and increased metabolic function in the brain. The NGF studies continue today, with Phase 2, multi-center studies currently underway.

"NGF therapy aims to stimulate the function of specific cholinergic neurons, which are like the air traffic controllers of the brain, helping to direct the activities of cells in broad regions of the brain," Tuszynski explained. However, he added that the benefits of NGF therapy, if validated in ongoing trials, will not be curative. Eventually, the effect of the NGF "boost" will be countered by the widespread death of neurons in the cerebral cortex as a result of advancing Alzheimer's disease.

"In contrast, BDNF acts directly on dying cells in specific memory circuits of the brain," Tuszynski said. "In this series of studies, we have shown that BDNF targets the cortical cells themselves, preventing their death, stimulating their function, and improving learning and memory. Thus, BDNF treatment can potentially provide long-lasting protection by slowing, or even stopping disease progression in the cortical regions that receive treatment."

The protective and restorative effects of BDNF occurred independently of the build-up of amyloid, a protein that accumulates in the brain to form plaques in Alzheimer's disease. Many current experimental treatments for Alzheimer's disease target amyloid production, so the potential role of BDNF as an alternative protective intervention is of great potential interest, said Tuszynski. Because BDNF targets a different set of disease mechanisms than amyloid modulation, there is also potential to combine BDNF and amyloid-based treatments, theoretically providing a two-pronged attack on the disease.

The study was supported by the National Institutes of Health, the California Regional Primate Research Center, the Veterans Administration, the Alzheimer's Association, the State of California, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Shiley Family Foundation. Tuszynski is scientific founder of Trophin Therapeutics, a company that may potentially benefit from the research results.

Study co-authors are Alan H. Nagahura, David A. Merrill, Shingo Tsukada, Brock E. Schroeder, Gideon M. Shaked, Ling Want, Armin Blesch, James M. Conner, Edward Rockenstein, Edward H. Koo, and Eliezer Masliah of the UC San Diego Department of Neurosciences, and Andrea A. Chiba of the UC San Diego Departments of Neurosciences and Cognitive Science. Giovanni Coppola and Daniel Geschwind of the Program in Neurogenetics, Department of Neurology at UCLA, and Albert Kim and Moses V. Chao, Skirball Institute of Biomolecular Medicine at New York University School of Medicine.

Getting Diabetes Before 65 More Than Doubles Risk For Alzheimer's Disease

Diabetics have a significantly greater risk of dementia, both Alzheimer's disease — the most common form of dementia — and other dementia, reveals important new data from an ongoing study of twins. The risk of dementia is especially strong if the onset of diabetes occurs in middle age, according to the study.
"Our results . . . highlighted the need to maintain a healthy lifestyle during adulthood in order to reduce the risk of dementia late in life," explained Dr. Margaret Gatz, who directs the Study of Dementia in Swedish Twins.

In a study published in the journal Diabetes, Gatz and researchers from Sweden show that getting diabetes before the age of 65 corresponds to a 125 percent increased risk for Alzheimer's disease. Nearly 21 million people in the United States have diabetes, according to the American Diabetes Association, which publishes the journal.

This risk of Alzheimer's disease or other dementia was significant for mid-life diabetics — as opposed to those who develop diabetes after 65 — even when controlling for family factors. In other studies, genetic factors and childhood poverty have been shown to independently contribute to the risk of both diabetes and dementia.

"Twins provide naturally matched pairs, in which confounding factors such as genetics and childhood environment may be removed when comparisons are made between twins," explained Gatz, professor of psychology, gerontology and preventive medicine at the University of Southern California and foreign adjunct professor of medical epidemiology and biostatistics at the Karolinska Institute in Sweden.

Indeed, the chances of a diabetic developing Alzheimer's disease may be even greater in real life than in the study, the researchers write. They identify several factors that might have led them to underestimate the risk of dementia and Alzheimer's among those who develop diabetes before the age of 65.

Diabetes usually appears at a younger age than dementia does, the researchers note. Diabetes is also associated with a higher mortality rate, which may reduce the size of the sample of older adults. In addition, approximately 30 percent of older adults with diabetes have not been diagnosed.

The results of the study implicate adult choices such as exercise, diet and smoking, as well as glycemic control in patients with diabetes, in affecting risk for Alzheimer's disease and diabetes, according to the researchers.

The sample for the study was 13,693 Swedish twins aged 65 or older in 1998, the year tracking for dementia began. Information about diabetes came from prior surveys of twins and linkage to hospital discharge registry data beginning in the 1960s.

Weili Xu of the Karolinska Institute was the lead author of the study, which was a part of her dissertation research.

The research was supported by grants from the National Institute on Aging, the Alzheimer's Association (U.S.A.), the Swedish Research Council in Medicine, and Swedish Brain Power.

Antipsychotic Drugs Double Risk Of Death Among Alzheimer's Patients

New research into the effects of antipsychotic drugs commonly prescribed to Alzheimer’s patients concludes that the medication nearly doubles risk of death over three years.

The study, funded by the Alzheimer’s Research Trust, was led by Prof Clive Ballard’s King’s College London team and is published in Lancet Neurology on 9 January.

The study involved 165 Alzheimer’s patients in care homes who were being prescribed antipsychotics. 83 continued treatment and the remaining 82 had it withdrawn and were instead given oral placebos.

Findings showed a significant increase in risk of death for patients who continued taking antipsychotic medication. The difference between the two groups became more pronounced over time, with 24-month survival rates for antipsychotic-treated patients falling to 46% versus 71% on the placebo and at 36 months it was 30% versus 59%. It means that after three years, less than a third of people on antipsychotics were alive compared to nearly two thirds using the dummy drug.

Antipsychotics are used to treat symptoms of agitation, delusions and aggressive behaviour. NICE guidelines recommend that the drugs should only be used for short periods of time and where symptoms are severe, and should be very carefully monitored, although in clinical practice the average length of prescription is 1-2 years. While there is evidence of modest short-term (6-12 weeks) benefits of antipsychotic treatment for the serious behavioural symptoms of Alzheimer’s, a previous Alzheimer’s Research Trust study showed that these benefits were not evident over longer periods of treatment.

As many as 100,000 people with dementia are routinely prescribed antipsychotics in UK care homes. It could mean 23,500 people dying prematurely, according to a 2008 report by Paul Burstow MP.

Prof Clive Ballard of King’s College London said: “The results further highlight the need to seek less harmful alternatives for the long-term treatment of behavioural symptoms in Alzheimer’s patients. At the moment, there is still a limited place for antipsychotics in the treatment of Alzheimer’s, particularly severe aggression, but the serious concerns of the drugs shown by our research emphasise the urgent need to put an end to unnecessary and prolonged prescribing”.

Rebecca Wood, Chief Executive of the Alzheimer’s Research Trust, said: “The findings of this research are a real wake-up call and underline the danger of prescribing antipsychotics long-term for anything other than exceptional circumstances. We must avoid the use of these drugs as a potentially dangerous ‘chemical cosh’ to patients who would be better off without it. The study also highlights the urgent need to develop better treatments as Alzheimer’s patients have few options available to them.

"700,000 people in the UK have dementia; we urgently need to fund more research to develop the new treatments we so desperately need”.

Dr Mark Baxter of the University of Oxford added: "Antipsychotic drugs can be effective in controlling unpleasant and disturbing behavioural symptoms of Alzheimer's disease, including severe aggression, delusions, and agitation. But this study shows, conclusively, that these drugs have a severe and serious cost in terms of increased mortality. The study follows the gold-standard double-blind, placebo-controlled method for clinical trials, and is unique in examining long-term effects of antipsychotic treatment on mortality in patients with Alzheimer's disease.

"Antipsychotics do not have any effects on the underlying disease processes of Alzheimer's disease. What is needed is not only an increased application of non-drug methods to improve behavioural health in patients with dementia -- including cognitive-behavioural therapy and environmental design -- as well as a better understanding of how Alzheimer's neuropathology causes behavioural disturbances in addition to its effects on memory, so that rational drug therapies can be developed that do not have the liabilities of currently-available antipsychotics."