Studying Down Syndrome Might Help Us Better Understand Alzheimer’s Disease

By Elizabeth Head, Associate Professor at University of Kentucky

Alzheimer’s disease is the most common form of dementia in older adults. At the moment there is no cure, but many clinicians feel that the earlier one is diagnosed, the better the possibilities are for treatment or slowing the disease.

But developing treatments or prevention approaches for Alzheimer’s disease is difficult. There is no biomarker (for example a blood test) or definitive medical test for it and there is no set age where people develop memory impairments and dementia. [Read more…]

Alzheimer’s Diagnostic Guidelines Updated for First Time in 27 Years

For the first time in 27 years, clinical diagnostic criteria for Alzheimer’s disease dementia have been revised, and research guidelines for earlier stages of the disease have been characterized to reflect a deeper understanding of the disorder.

The National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines for Alzheimer’s Disease outline some new approaches for clinicians and provides scientists with more advanced guidelines for moving forward with research on diagnosis and treatments. They mark a major change in how experts think about and study Alzheimer’s disease. Development of the new guidelines was led by the National Institutes of Health and the Alzheimer’s Association.

The original criteria were the first to address the disease and described only later stages, when symptoms of dementia are already evident. The updated guidelines announced today cover the full spectrum of the disease as it gradually changes over many years. They describe the earliest preclinical stages of the disease, mild cognitive impairment, and dementia due to Alzheimer’s pathology. Importantly, the guidelines now address the use of imaging and biomarkers in blood and spinal fluid that may help determine whether changes in the brain and those in body fluids are due to Alzheimer’s disease. Biomarkers are increasingly employed in the research setting to detect onset of the disease and to track progression, but cannot yet be used routinely in clinical diagnosis without further testing and validation.

“Alzheimer’s research has greatly evolved over the past quarter of a century. Bringing the diagnostic guidelines up to speed with those advances is both a necessary and rewarding effort that will benefit patients and accelerate the pace of research,” said National Institute on Aging Director Richard J. Hodes, M.D.

“We believe that the publication of these articles is a major milestone for the field,” said William Thies, Ph.D., chief medical and scientific officer at the Alzheimer’s Association. “Our vision is that this process will result in improved diagnosis and treatment of Alzheimer’s, and will drive research that ultimately will enable us to detect and treat the disease earlier and more effectively. This would allow more people to live full, rich lives without — or with a minimum of — Alzheimer’s symptoms.”

The new guidelines appear online April 19, 2011 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. They were developed by expert panels convened last year by the National Institute on Aging (NIA), part of the NIH, and the Alzheimer’s Association. Preliminary recommendations were announced at the Association’s International Conference on Alzheimer’s Disease in July 2010, followed by a comment period.

Guy M. McKhann, M.D., Johns Hopkins University School of Medicine, Baltimore, and David S. Knopman, M.D., Mayo Clinic, Rochester, Minn., co-chaired the panel that revised the 1984 clinical Alzheimer’s dementia criteria. Marilyn Albert, Ph.D., Johns Hopkins University School of Medicine, headed the panel refining the MCI criteria. Reisa A. Sperling, M.D, Brigham and Women’s Hospital, Harvard Medical School, Boston, led the panel tasked with defining the preclinical stage. The journal also includes a paper by Clifford Jack, M.D., Mayo Clinic, Rochester, Minn., as senior author, on the need for and concept behind the new guidelines.

The original 1984 clinical criteria for Alzheimer’s disease, reflecting the limited knowledge of the day, defined Alzheimer’s as having a single stage, dementia, and based diagnosis solely on clinical symptoms. It assumed that people free of dementia symptoms were disease-free. Diagnosis was confirmed only at autopsy, when the hallmarks of the disease, abnormal amounts of amyloid proteins forming plaques and tau proteins forming tangles, were found in the brain.

Since then, research has determined that Alzheimer’s may cause changes in the brain a decade or more before symptoms appear and that symptoms do not always directly relate to abnormal changes in the brain caused by Alzheimer’s. For example, some older people are found to have abnormal levels of amyloid plaques in the brain at autopsy yet never showed signs of dementia during life. It also appears that amyloid deposits begin early in the disease process but that tangle formation and loss of neurons occur later and may accelerate just before clinical symptoms appear.

To reflect what has been learned, the National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines for Alzheimer’s Disease cover three distinct stages of Alzheimer’s disease:

  • Preclinical — The preclinical stage, for which the guidelines only apply in a research setting, describes a phase in which brain changes, including amyloid buildup and other early nerve cell changes, may already be in process. At this point, significant clinical symptoms are not yet evident. In some people, amyloid buildup can be detected with positron emission tomography (PET) scans and cerebrospinal fluid (CSF) analysis, but it is unknown what the risk for progression to Alzheimer’s dementia is for these individuals. However, use of these imaging and biomarker tests at this stage are recommended only for research. These biomarkers are still being developed and standardized and are not ready for use by clinicians in general practice.
  • Mild Cognitive Impairment (MCI) — The guidelines for the MCI stage are also largely for research, although they clarify existing guidelines for MCI for use in a clinical setting. The MCI stage is marked by symptoms of memory problems, enough to be noticed and measured, but not compromising a person’s independence. People with MCI may or may not progress to Alzheimer’s dementia. Researchers will particularly focus on standardizing biomarkers for amyloid and for other possible signs of injury to the brain. Currently, biomarkers include elevated levels of tau or decreased levels of beta-amyloid in the CSF, reduced glucose uptake in the brain as determined by PET, and atrophy of certain areas of the brain as seen with structural magnetic resonance imaging (MRI). These tests will be used primarily by researchers, but may be applied in specialized clinical settings to supplement standard clinical tests to help determine possible causes of MCI symptoms.
  • Alzheimer’s Dementia — These criteria apply to the final stage of the disease, and are most relevant for doctors and patients. They outline ways clinicians should approach evaluating causes and progression of cognitive decline. The guidelines also expand the concept of Alzheimer’s dementia beyond memory loss as its most central characteristic. A decline in other aspects of cognition, such as word-finding, vision/spatial issues, and impaired reasoning or judgment may be the first symptom to be noticed. At this stage, biomarker test results may be used in some cases to increase or decrease the level of certainty about a diagnosis of Alzheimer’s dementia and to distinguish Alzheimer’s dementia from other dementias, even as the validity of such tests is still under study for application and value in everyday clinical practice.

The panels purposefully left the guidelines flexible to allow for changes that could come from emerging technologies and advances in understanding of biomarkers and the disease process itself.

“The guidelines discuss biomarkers currently known, and mention others that may have future applications,” said Creighton H. Phelps, Ph.D., of the NIA Alzheimer’s Disease Centers Program. “With researchers worldwide striving to develop, validate and standardize the application of biomarkers at every stage of Alzheimer’s disease, we devised a framework flexible enough to incorporate new findings.”

Source: NIH

Beta-Amyloid Clearance from Brain May Underly Alzheimer’s Disease

Alzheimer’s disease is the most common cause of dementia in older adults, and affects as many as 5.1 million Americans. In Alzheimer’s disease, a protein fragment called beta-amyloid accumulates at abnormally high levels in the brain. In the the most common type of Alzheimer’s disease, late-onset Alzheimer’s, symptoms usually appear after age 65.

Now researchers have found that in late-onset Alzheimer’s disease, beta-amyloid is produced in the brain at a normal rate but is not cleared, or removed from the brain, efficiently. [Read more…]

Elderly with Untreated Vision Problem More Likely to Develop Alzheimer’s

Elderly people with visual disorders that are left untreated are significantly more likely to develop Alzheimer’s disease — the most common form of dementia, according to a University of Michigan Health System study.

The study used Medicare data and shows that those with poor vision who visited an ophthalmologist at least once for an examination were 64 percent less likely to develop dementia.

The study appears online ahead of print in the American Journal of Epidemiology and may draw a new picture of poor vision as predictor of dementia rather than as a symptom after the diagnosis.

“Visual problems can have serious consequences and are very common among the elderly, but many of them are not seeking treatment,” says lead author Mary A.M. Rogers, Ph.D, research assistant professor of internal medicine at the U-M Medical School and research director of the Patient Safety Enhancement Program at the U-M Health System and the Ann Arbor VA Medical Center.

For the study, Rogers and her colleague Kenneth M. Langa, M.D., Ph.D., professor of internal medicine at U-M Medical School, analyzed data from the nationally representative Health and Retirement Study and records from Centers for Medicare and Medicaid Services.

”Our results indicate that it is important for elderly individuals with visual problems to seek medical attention so that the causes of the problems can be identified and treated,” Rogers says.

The types of vision treatment that were helpful in lowering the risk of dementia were surgery to correct cataracts and treatments for glaucoma, retinal disorders and other eye-related problems.

Proper vision is a requirement for many of the activities that previously have been found to lower the risk of Alzheimer’s disease. These include reading, playing board games, other mentally stimulating activities, social networking, as well as physical activity such as walking and routine exercising. A visual disorder may interfere with normal mobility and may also hinder a person’s ability to participate in such activities.

“Many elderly Americans do not have adequate health coverage for vision, and Medicare does not cover preventative vision screenings for most beneficiaries,” Rogers says. “So it’s not unusual that the elderly receive vision treatment only after a problem is severe enough to warrant a visit to the doctor when the problem is more advanced.”

According to a survey conducted by the National Eye Health Education Program, less than 11 percent of respondents understood that there are no early warning signs for eye problems such as glaucoma and diabetic retinopathy.

However, vision problems and blindness are among the top 10 disabilities among adults and can result in a greater tendency to experience other health conditions or even to die prematurely.

“While heart disease and cancer death rates are continuing to decline, mortality rates for Alzheimer’s disease are on the rise,” says Rogers. “So if we can delay the onset of dementia, we can save individuals and their families from the stress, cost and burden that are associated with Alzheimer’s disease.”

The study was based on the surveys and medical information from 625 people compiled from 1992-2005. Only 10 percent of Medicare beneficiaries who developed dementia had excellent vision at the beginning of the study, while 30 percent of those who maintained normal cognition had excellent vision at the onset of the study.

One in five Americans who are over age 50 report experiencing a visual impairment, according to the U.S. Centers for Disease Control and Prevention. Approximately 5 million Americans have Alzheimer’s disease and the number has doubled since 1980. It is expected to be as high as 13 million by 2050.

Source: American Journal of Epidemiology,/em> 2010 Feb. 11; doi:10.1093; University of Michigan

Scientists’ Research May Help ID Eary Markers for Alzheimer’s Disease

Alzheimer’s disease patients show a relentless decline in memory over the course of the disease, which is accompanied by both brain atrophy and by characteristic deposits in the brain tissue called amyloid plaques and neurofibrillary tangles.

Researchers from the Chinese Academy of Sciences studied a large database, collected in the US, of patients with Alzheimer’s or memory complaints who had MRI scans and had spinal taps to collect cerebrospinal fluid, which is in the brain and spinal chord. By examining the CFS they could measure the amounts of the substances that make p plaques and tangles, and related this to brain atrophy.

They found that the amount of plaque and tangle-producing chemicals in the cerebrospinal fluid correlated with brain tissue loss in selective regions of the brain which are typically affected in Alzheimer’s disease. The brains in these regions had thinned out suggesting that brain cells had died. These regions are important for memory and are typically active when the brain is at rest.

Using these techniques may ultimately help identify early markers of disease in Alzheimer’s, potentially indicating who is likely to develop Alzheimer’s before memory loss is critical.

Authors: J Jiang, S Wang, X Zhen, Z Yao, C Xu, T Jiang, AD NI3 LIAMA Center for Computational Medicine, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, 100190, Beijing, China

Source: Organization for Human Brain Mapping

Simple Blood Test May Identify People At Risk Of Developing Alzheimer’s Disease

A 20-year study by researchers at Columbia University Medical Center has found that a simple blood test may identify people at risk of developing Alzheimer’s Disease. These ground-breaking findings could change the way the disease is treated or someday prevent it.

The findings indicate that people with elevated levels of a certain peptide in the blood plasma, Amyloid Beta 42 (Aß42), are at increased risk of developing Alzheimer’s disease. Conversely, a decline of Aß42 in the bloodstream may signal the compartmentalization or “traffic jam” of Aß42 in the brain, which occurs in the brains of people with Alzheimer’s.

“To date, Aß42 levels have measured most reliably in the cerebrospinal fluid, which is more difficult to collect than blood,” said Nicole Schupf, Ph.D., Dr.P.H., associate professor of clinical epidemiology at Columbia University Medical Center and lead author of the paper. “Blood draws can be done with relative ease and greater frequency than spinal taps, which is typically the way cerebrospinal fluid is collected.”

The study showed researchers that plasma levels of Aß42 appear to increase before the onset of Alzheimer’s disease and decline shortly after the onset of dementia. They deduce that Aß42 trapped in the brain could account for the decrease in levels post-dementia. Richard Mayeux, M.D., M.S., professor of neurology, psychiatry, and epidemiology, and co-director of the Taub Institute of Research on Alzheimer’s Disease and the Aging Brain at CUMC, led the Northern Manhattan study, and compares findings finding to something similar seen in heart attack patients, who typically have elevated lipid levels in their bloodstream prior to a heart attack, but decreased post-heart attack lipid levels.

Dr. Mayeux, the senior author of this paper, reported that, using more specific antibodies developed by the Ravetch Laboratory at Rockefeller University, the research team isolated the most harmful form of amyloid compound, the protofibrillar form of Aß. While the cognitive impairments of Alzheimer’s can be monitored throughout the disease course, clinicians have had no reliable way to monitor the pathologic progression of the disease.

Being able to reliably measure Aß levels in the blood could provide clinicians with a tool that forecasts the onset of Alzheimer’s much earlier. Earlier detection would of course be an important step in combating the disease, researchers said.

Source: Proceedings of the National Academy of Sciences, Sept. 8, 2008

Mental Abilities Weaken Long Before Death, Despite Absence of Dementia

A new study finds that a decline in older people’s’ mental abilities starts years before death, even if they do not have dementia.

“These changes are different and separate from the changes in thinking skills that occur as people get older,” said study author Valgeir Thorvaldsson, MSc, of Göteberg University in Sweden. “We found accelerated changes in people’s mental skills that indicated a terminal decline phase years before death.”

Perceptual speed starts deteriorating some 15 years before death, spatial ability starts failing nearly 8 years before death, and verbal ability about 6.5 years before death. These findings came out of a study using 288 people without dementia, who were monitored from age 70 to death, with an average age at death of 84. Their mental skills were checked up to 12 times over a 30-year period, to ensure they did not have dementia.

Said Thorvaldsson: “Cardiovascular conditions such as heart disease or dementia that is too early to be detected could be factors,” he said. “Increased health problems and frailty in old age often lead to inactivity, and this lack of exercise and mental stimulation could accelerate mental decline.”

Thorvaldsson also noted that verbal abilities declined sharply in the terminal phase and did not decline significantly due to age only. “This indicates that people remain stable in their verbal abilities unless they are experiencing disease processes that also increase their mortality risk,” he said. “A change in verbal ability might therefore be considered a critical marker for degeneration in health in older people.”

Source: Neurology, the medical journal of the American Academy of Neurology, August 27, 2008, online edition.

Eating Fish May Avert Memory Loss

The risk of cognitive decline and stroke in older adults may be reduced by eating tuna and other kinds of fish, according to study by researchers in Finland.

The study used a sample of 3,660 men and women aged 65 or older and subjected them to brain scans to look for silent brain infarcts, stroke or dementia. 5 years later, 2,313 members of the sample were tested again with scans, and all participants were given questionnaires on fish in their diets.

Findings of the study showed that participants who ate broiled or baked tuna or other fish high in omega-3 fatty acids (DHA and EPA) three or more times a week were at a 26% lower risk of experiencing the silent brain lesions that cause dementia and stroke than people who were not regular fish eaters. Even one fish meal weekly reduced the risk by 13%, and the study found that regular consumption of these types of fish reduced the changes of white matter in the brains of fish eaters.

“While eating tuna and other types of fish seems to help protect against memory loss and stroke, these results were not found in people who regularly ate fried fish,” said Jyrki Virtanen, PhD, RD, with the University of Kuopio in Finland. “More research is needed as to why these types of fish may have protective effects, but the omega-3 fatty acids EPA and DHA would seem to have a major role.” Types of fish that contain high levels of DHA and EPA nutrients include salmon, mackerel, herring, sardines, and anchovies.

“Previous findings have shown that fish and fish oil can help prevent stroke, but this is one of the only studies that looks at fish’s effect on silent brain infarcts in healthy, older people,” said Virtanen. Research shows that silent brain infarcts, which are only detected by brain scans, are found in about 20 percent of otherwise healthy elderly people.

Source: Neurology, August 5, 2008

Alzheimer’s Disease Risk Different for Men and Women

Recent research suggests that the chances of developing Alzheimer’s Disease are different for men and women, with stroke in men and depression in women being key elements.

The research was conducted in France, among 7,000 people aged 65 and over, drawn from the general population. While none of the participants had dementia, some 40% had mild cognitive impairment. Four years later 6.5% of those displaying mild cognitive impairment had developed dementia, while no change was noted in just over half. About one third returned to normal cognitive ability.

The move from cognitive impairment to dementia however, was marked among subjects taking anticholinergic drugs for depression. A variation in the ApoE gene, a known risk factor for dementia, was also more common among those whose mild cognitive impairment progressed.

The results demonstrated that men with mild cognitive impairment were probably overweight and diabetic, and to have suffered a stroke. In fact, male stroke victims were three times as likely to progress from cognitive impairment to dementia.

Women with mild cognitive impairment had poorer general health, were disabled, and suffered from insomnia, besides having an inadequate support group. They were also unable to perform the daily tasks that would enable them to live alone without assistance. It was judged they were 3.5 times as likely to develop dementia, while those suffering from depression were twice as likely to do so. Stroke was not a risk factor for women, although there was similar rate of occurrence in men and women.

Source: Journal of Neurology, Neurosurgery, and Psychology, 2008; doi 10.1136/jnnp.2007.136903

Alzheimer’s Disease Connection to Stroke Explained

The risk of Alzheimer’s disease is nearly doubled among people who have had a stroke, and researchers at Columbia University Medical Center have found a process in the brain that explains the connection.

There is an increase in the production of the toxic amyloid beta (Aß) peptides after a stroke that are believed to cause Alzheimer’s disease. Results in this study showed that Aß production rises when there is an increase in production of a peptide called p25, which occurs in rodents and humans following a stroke. The Columbia team identified a pathway, known as p25/cdk5, whereby higher levels of p25 led to enhanced activity of a molecule called cdk5, which in turn led to a rise in the production of Aß

By reducing the activity of cdk5, by either an inhibitor or by genetic manipulation, lead author Karen found a decrease in Aß production in the brain, demonstrating that the p25/cdk5 pathway may be a treatment target for Alzheimer’s disease. Specifically, inhibitors of cdk5 are particular candidates for therapeutic development.

"This finding connects the dots between p25 and increased production of amyloid beta, and this p25/cdk5 pathway could explain why the risk of Alzheimer’s disease is significantly higher following a stroke," said Dr. Duff, professor of pathology (in psychiatry and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain) at Columbia University Medical Center and the New York State Psychiatric Institute. "However, we still need to verify that this pathway is actually set in motion after a stroke; right now the data is still circumstantial."

Dr. Duff’s laboratory is currently working on experiments to verify this pathway’s involvement using human post-mortem tissue of stroke patients. The specific pathway investigated was shown to be most active in young mice, as compared to older mice suggesting that p25/cdk5 may not be implicated in late-onset Alzheimer’s disease, the most common form of this neurodegenerative disease.

The research was published in the March 13, 2008 issue of Neuron.