Research illuminates why stimulating environment may protect against Alzheimer's disease

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Medical News

 

"Use it or lose it." The saying could apply especially to the brain when it comes to protecting against Alzheimer's disease. Previous studies have shown that keeping the mind active, exercising and social interactions may help delay the onset of dementia in Alzheimer's disease.

Now, a new study led by Dennis Selkoe, MD, co-director of the Center for Neurologic Diseases in the BWH Department of Neurology, provides specific pre-clinical scientific evidence supporting the concept that prolonged and intensive stimulation by an enriched environment, especially regular exposure to new activities, may have beneficial effects in delaying one of the key negative factors in Alzheimer's disease.
The study will be published online on March 6, 2013 in Neuron.
Alzheimer's disease occurs when a protein called amyloid beta accumulates and forms "senile plaques" in the brain. This protein accumulation can block nerve cells in the brain from properly communicating with one another. This may gradually lead to an erosion of a person's mental processes, such as memory, attention, and the ability to learn, understand and process information.
The BWH researchers used a wild-type mouse model when evaluating how the environment might affect Alzheimer's disease. Unlike other pre-clinical models used in Alzheimer's disease research, wild-type mice tend to more closely mimic the scenario of average humans developing the disease under normal environmental conditions, rather than being strongly genetically pre-disposed to the disease.
Selkoe and his team found that prolonged exposure to an enriched environment activated certain adrenalin-related brain receptors which triggered a signaling pathway that prevented amyloid beta protein from weakening the communication between nerve cells in the brain's "memory center," the hippocampus. The hippocampus plays an important role in both short- and long-term memory.
The ability of an enriched, novel environment to prevent amyloid beta protein from affecting the signaling strength and communication between nerve cells was seen in both young and middle-aged wild-type mice.

"This part of our work suggests that prolonged exposure to a richer, more novel environment beginning even in middle age might help protect the hippocampus from the bad effects of amyloid beta, which builds up to toxic levels in one hundred percent of Alzheimer patients," said Selkoe. Moreover, the scientists found that exposing the brain to novel activities in particular provided greater protection against Alzheimer's disease than did just aerobic exercise. According to the researchers, this observation may be due to stimulation that occurred not only physically, but also mentally, when the mice moved quickly from one novel object to another.
"This work helps provide a molecular mechanism for why a richer environment can help lessen the memory-eroding effects of the build-up of amyloid beta protein with age," said Selkoe. "They point to basic scientific reasons for the apparent lessening of AD risk in people with cognitively richer and more complex experiences during life."
Source: Brigham and Women's Hospital

Antiviral drugs could slow Alzheimer's disease

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University of Manchester

Antiviral drugs used to target the herpes virus could be effective at slowing the progression of Alzheimer’s disease (AD), a new study shows.

The University of Manchester scientists have previously shown that the herpes simplex virus type 1 (HSV1) is a risk factor for Alzheimer’s when it is present in the brains of people who have a specific genetic risk to the disease.

AD is an incurable neurodegenerative condition affecting about 18 million people worldwide. The causes of the disease or of the abnormal protein structures seen in AD brains – amyloid plaques and neurofibrillary tangles – are completely unknown.

The Manchester team has established that the herpes virus causes accumulation of two key AD proteins – β-amyloid (Aβ) and abnormally phosphorylated tau (P-tau) – known to be the main components of plaques and tangles respectively. Both proteins are thought by many scientists to be involved in the development of the disease.

“We have found that the viral DNA in AD brains is very specifically located within amyloid plaques,” said Professor Ruth Itzhaki, who led the team in the University’s Faculty of Life Sciences. “This, together with the production of amyloid that the virus induces, suggests that HSV1 is a cause of toxic amyloid products and of plaques.

“Our results suggest that HSV1, together with the host genetic factor, is a major risk for AD, and that antiviral agents might be used for treating patients to slow disease progression.”

Currently available antiviral agents act by targeting replication of HSV1 DNA, and so the researchers considered that they might be successful in treating AD only if the accumulation of β-amyloid and P-tau accumulation caused by the virus occurs at or after the stage at which viral DNA replication occurs.

“If these proteins are produced independently of HSV1 replication, antivirals might not be effective,” said Professor Itzhaki. “We investigated this and found that treatment of HSV1-infected cells with acyclovir, the most commonly used antiviral agent, and also with two other antivirals, did indeed decrease the accumulation of β-amyloid and P-tau, as well as decreasing HSV1 replication as we would expect.

“This is the first study investigating antiviral effects on AD-like changes and we conclude that since antiviral agents reduce greatly β-amyloid and P-tau levels in HSV1-infected cells, they would be suitable for treating Alzheimer’s disease. The great advantage over current AD therapies is that acyclovir would target only the virus, not the host cell or normal uninfected cells. Further, these agents are very safe and are relatively inexpensive.

“Also, by targeting a cause of Alzheimer’s disease, other viral damage, besides β-amyloid and P-tau, which might be involved in the disease’s pathogenesis, would also be inhibited.

“The next stage of our research – subject to funding – will focus on finding the most suitable antiviral agent – or combination of two agents that operate via different mechanisms – for use as treatment. We then need to investigate the way in which the virus and the genetic risk factor interact to cause the disease, as that might lead to further novel treatments.

“Eventually, we hope to begin clinical trials in humans but this is still some way off yet and again will require new funding.”

The study, carried out with Dr Matthew Wozniak and other colleagues in the Faculty of Life Sciences, is published in the Public Library of Science (PLoS) One journal

Gantenerumab: New Alzheimer's drug shows early promise

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USA Today

The new study, which appears online Oct. 10 in the Archives of Neurology, is among the first to show the effects of an anti-amyloid drug in humans with Alzheimer's disease, but experts caution that while promising, more research is needed before this drug can be deemed safe or effective.
And, in what may turn out to be an equally important caveat, experts also say that it's by no means certain that reducing levels of amyloid plaque would stave off memory loss and the other mental declines associated with the disease because the role of the plaque in Alzheimer's isn't fully understood.
Alzheimer's disease is the most common form of dementia. Symptoms including serious memory loss, confusion and mood changes develop gradually and worsen with time. Recently, many strides have been made in diagnosing Alzheimer's disease earlier, but doctors have been stymied by a lack of effective treatments to stop or slow the course of the disease.
It's long been known that a protein fragment called beta-amyloid builds up in the spaces between nerve cells in the brains of people with Alzheimer's disease. The new drug, gantenerumab, targets these amyloid proteins by priming the body's immune system to recognize them as invaders.
Of 16 people with mild-to-moderate Alzheimer's disease, those who received two to seven infusions of the experimental drug every four weeks showed marked reductions in the amount of plaque in their brains via imaging tests that were conducted several months after their treatments.
By contrast, amyloid load increased among people who were randomized to receive the placebo. The new drug was given at either 60 or 200 milligrams (mg) doses. The higher dose yielded greater reductions in amyloid levels, the study showed. People who were given the 60 mg doses saw a nearly 16 percent reduction in the amount of amyloid, and those given the 200 mg doses saw a 36 percent reduction. The new study was conducted and funded by the drug's manufacturer, F. Hoffmann-LaRoche Ltd., in Basel, Switzerland.
The big question is whether or not reducing amyloid levels has any effect on the symptoms or progression of Alzheimer's disease, said Dr. Patrick Lyden, chief of neurology at Cedars-Sinai Medical Center in Los Angeles. "There is a growing concern that amyloid is a guilty bystander, but not the actual culprit in the brains of people with Alzheimer's disease, and taking away the bystander may not help the patient," he said.
There are approximately one dozen therapies, including vaccines, for Alzheimer's disease that are currently in the pipeline, Lyden noted. "They are all extremely exciting and promising in animals," he said. "This is the first one to show a preliminary result in people, but we have a huge way to go to make sure it is safe and improves symptoms."
Many in the Alzheimer's research community are awaiting these drugs with bated breath, but "none are ready for prime time," he said.
The leading theory of Alzheimer's disease is that an imbalance in the production or clearance of the amyloid plaque in the brain initiates a cascade of events that lead to dementia, explained Dr. Neelum Aggarwal, an associate professor of neurological sciences at Rush Alzheimer's Disease Research Center at Rush University Medical Center in Chicago.
"Accumulation of the plaques cause a variety of cellular responses: inflammation, neuronal death, and thus any potential treatment that can alter these processes would be beneficial," she said. The hope is that gantenerumab or other drugs like it will not only prevent amyloid from accumulating in the brain, but also slow down the cognitive impairment that occurs in people with Alzheimer's disease, she added.
That said, these experimental drugs carry the potential for serious side effects, including causing the immune system to go haywire. "The main issue that remains for this type of drug development is managing the immune response," Aggarwal said. Other side effects include a potentially fatal fluid build-up in certain areas of the brain. "This is problematic in that use of these treatments may carry a very high risk for neurologic complications, thus necessitating heightened monitoring, and diminishing its applicability as a treatment for a larger patient population such as the Alzheimer's disease population," she said.
If any of these drugs make it through the pipeline, it also needs to be determined who will get them, including whether the drugs will be given to prevent Alzheimer's in patients at high-risk of the disease or to treat it once it's started.
The need for a drug to delay the onset or slow progression of Alzheimer's disease can't be underestimated, Aggrawal said. In the United States alone, there are 5.4 million people with Alzheimer's disease, and the numbers are expected to increase to 13 million by 2050, when approximately three of every five people over the age of 85 will have Alzheimer's disease, she said.

Alzheimer's disease looks different in people over 80

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Medscape Today

Alzheimer's disease (AD) may be more difficult to detect in people older than 80 years, suggest results of a new study, because disease presentation may be different than that seen in the larger population of patients.

"The typical pattern of AD-related cognitive and morphometric changes seen in the young old appear to be less salient in the very old," first author Nikki H. Stricker, PhD, from the Veterans Affairs Boston Healthcare System and the Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, and colleagues report.

"Thus, mild cases of AD in the very old may go undetected if one expects to see the prototypical pattern and severity of cognitive or brain changes that occur in the young old with AD," they conclude.

This study highlights "the importance of paying attention to age when reviewing cognitive test performances and in reviewing other possible biomarkers of Alzheimer's disease such as neuroimaging scans," coauthor Mark W. Bondi, PhD, from the Psychology Service, Veterans Affairs San Diego Healthcare System, San Diego, California, noted in comments to Medscape Medical News.

Their results are published online August 10 in Neurology.

Signs, Symptoms More Subtle in 80-Plus Group

The researchers compared hippocampal volume and cortical gray matter thickness in areas known to be affected by AD in 105 patients with AD and 125 healthy control participants. Participants between 60 and 75 years old made up the "young-old" group, whereas those 80 years and older made up the "very-old" group. Among the 105 participants with AD, 64 were young-old, and 41 were very-old.

Brain morphometric and cognitive scores of the patients with AD were standardized to their respective age-appropriate healthy control subgroup and then compared, the researchers explain.

In the very-old, compared with the young-old, there was less severe cortical thinning in the left posterior cingulate cortex, right lateral temporal cortex, and bilateral parietal cortex, as well as in overall cortical thickness.

This finding is, in part, because these brain areas decrease in thickness as a result of aging. Therefore, there are fewer differences between the healthy very-old brain and the very-old brain with AD, the researchers point out.

"Our results indicate that overlap between normal and AD-related brain changes seen on magnetic resonance imaging (MRI) scans is greater in the very-old than in the young-old," Dr. Bondi said. "For example, the typical pattern of brain changes seen in an 85-year-old person with AD is less salient than in a 70-year old person with AD."

Similarly, several cognitive domains, including executive function, immediate memory, and attention/processing speed, were less abnormal in the very-old patients with AD relative to their young-old peers.

Broad Clinical Implications

"Clarification of how the presentation of AD changes with age may enhance our ability to detect early AD in the very-old, one of the fastest growing segments of the population," Dr. Bondi commented.

"Enhanced detection will be crucial for early application of interventions that may slow the disease process, thus preserving cognitive status, functional independence, and quality of life," he added.

Reached for comment, Rhoda Au, PhD, from the Department of Neurology, Boston University School of Medicine in Boston, Massachusetts, said "the most important broader implications" of this study are "its recognition of the developmental continuum extending to the very last years of life (and) that the elderly population cannot be characterized as a single subset population."

Dr. Au was not involved in the study but authored a linked commentary in the journal.

"As more and more people live into the 8th and 9th decades and beyond, the diagnostic and treatment practices applied to the younger old may not apply or work as effectively with the oldest old," she told Medscape Medical News.

The study was supported primarily by the National Institutes of Health (NIH) and the Dana Foundation. Dr. Stricker receives or has received research support from the Rosalind and Arthur Gilbert Foundation/American Federation for Aging Research and the NIH. Dr. Bondi serves as an associate editor for the Journal of the International Neuropsychological Society and receives research support from the Alzheimer's Association and the NIH. A complete list of author disclosures is listed in the original article. Dr. Au receives research support from the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and the Fogarty International Center.

Study: Lifelong stress increases risk of Alzheimer's disease

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LOGAN, UTAH, July 29, 2011 /NewsRelease/ - Chronic psychological stress throughout a lifespan might increase an individual’s risk for Alzheimer’s and dementia later in life, according to research from the Emma Eccles Jones College of Education and Human Services at Utah State University.

■Chronic Stress Produces Chemicals That Over Time Can Increase Rate of Neuronal Cell Death
■Stress Management Interventions Could Reduce Risk for Alzheimer’s
■Study Used Objective Data From a Recently Completed 15-Year Alzheimer’s Study
The research, led by Maria Norton, Ph.D., built off the recently completed 15-year Cache County Memory Study (CCMS) and used that data to focus on the role psychological stress has on dementia. The findings are consistent with the hypothesis that chronic stress can expose an individual to long-term levels of stress-related hormones, which results in chronically high levels of glucocorticoids, a natural chemical, shown in both animal and human studies to increase the rate of neuronal cell death with long-term exposure.

“Using this objective data, such as death records, medical information, and the cognitive evaluations from the CCMS, we were able to see that people who experienced particularly stressful life events, such as a parent’s death during one’s childhood, death of a child or spouse, or living with a spouse who is afflicted with dementia is associated with significantly higher rates of dementia later in life,” Norton said.

Norton also found that there were some factors that were associated with lower rates of depression and stress, such as individuals who had high levels of religious involvement, thus indicating that the ability to cope with psychological adversity might reduce the risk of Alzheimer’s.

“There are certainly some individuals who seem to weather stress and trials better than others, and as such they don’t tend to develop depression or face the long-term chronic exposure to the stress-related hormones that are linked to dementia,” added Norton. “This indicates that there may be preventative measures that can be taken to prevent or delay dementia. This study has helped us determine how to identify the more vulnerable subgroups of people who might benefit from stress management or other preventive interventions.”

Norton is an associate professor at Utah State University’s Department of Family, Consumer and Human Development. The Emma Eccles Jones College of Education is currently ranked fifth in the nation in terms of external funding for research.

The “Lifespan Stressors and Alzheimer’s Disease” study was funded by the National Institute on Aging. Findings from this study have been published in the Journal of the American Geriatrics Society, the Journals of Gerontology, and Age and Aging.