How do viruses affect Alzheimer's

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• Cell Press
• SWNS TV

American researchers found 'unusually high' levels of two strains of human herpes virus 6A (HHV-6A) and human herpes virus 7 (HHV-7) in brains of Alzheimer's sufferers, compared to those free of the disease. This opens up a robust array of new targets in the search for a cure to Alzheimer's. 

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The quest to understand what causes Alzheimer's disease--and to treat it--is complicated by the disease's long, slow progression and the difficulty of collecting brain tissue samples. But in a large-scale analysis published June 21 in the journal Neuron, researchers at the Icahn School of Medicine at Mount Sinai use data from three different brain banks to suggest that human herpesviruses are more abundant in the brains of Alzheimer's patients and may play a role in regulatory genetic networks that are believed to lead to the disease. This work lends support to the controversial hypothesis that viruses are involved in Alzheimer's disease and offers potential new paths for treatment.

"All I Found Were These Lousy Viruses"

"The title of the talk that I usually give is, 'I Went Looking for Drug Targets and All I Found Were These Lousy Viruses.' We didn't set out to find what we found. Not even close. We were trying to find drugs that could be repurposed to treat Alzheimer's patients, but the patterns that emerged from our data-driven analysis all pointed towards these viral biology themes," says co-senior author and geneticist Joel Dudley. who is also a member of the ASU-Banner Neurodegenerative Disease Research Center. 

The researchers analyzed data from three major brain banks courtesy of the National Institutes of Health's Accelerating Medicines Partnership - Alzheimer's Disease (AMP-AD) consortium, which allowed them to look at raw genomic data for large numbers of Alzheimer's patients in different cohorts. They constructed, mapped, and compared regulatory gene networks in areas of the brain known to be affected by Alzheimer's on multiple levels, looking at DNA, RNA, and proteins.

Search for Sequences from Hundreds of Different Viruses

"This kind of analysis was only possible because the consortium had coordinated for all of these other groups to put their sequencing data in the AMP-AD Knowledge Portal in a precompetitive environment that let us very quickly replicate our work across all these different cohorts. We needed access to sequences that are usually discarded in the course of studying the human genome. We needed to search for sequences from hundreds of different viruses, so having access to that raw, unprocessed data was absolutely key," says first author Ben Readhead. 

They found that human herpesvirus DNA and RNA were more abundant in the brains of those diagnosed postmortem with Alzheimer's disease and that abundance correlated with clinical dementia scores. And the two viruses they found to be most strongly associated with Alzheimer's, HHV-6A and HHV-7, were not as abundant in the brains of those with other neurodegenerative disorders. When they constructed networks that modeled how the viral genes and human genes interacted, they were able to show that the viral genes were regulating and being regulated by the human genes--and that genes associated with increased Alzheimer's risk were impacted.

Viruses are Accelerating the Brain Towards Alzheimer's

The brain is shown here as a complex network of interactions, with disruption of connections by the key viral species (HHV-6A, HHV-6B, HHV-7) identified in this study. (CREDIT: Readhead et al. Click to enlarge.)

"Previous studies of viruses and Alzheimer's have always been very correlative. But we were able to do statistical causal inference testing and more sophisticated analysis, which allowed us to identify how the viruses are directly interacting with or coregulating or being regulated by Alzheimer's genes. I don't think we can answer whether herpesviruses are a primary cause of Alzheimer's disease. But what's clear is that they're perturbing networks and participating in networks that directly accelerate the brain towards the Alzheimer's topology," says Dudley. 

The researchers believe that their findings align with other current research in the Alzheimer's field on the role of innate immunity in the disease, particularly recent findings that beta-amyloid protein--the culprit behind the plaques that build up in the Alzheimer's-affected brain--may accumulate as part of a defense against infections. In their study, they found that herpesviruses were involved in networks that regulate amyloid precursor proteins.

No New Worries

They argue, however, that their work shouldn't make anyone worried. "While these findings do potentially open the door for new treatment options to explore in a disease where we've had hundreds of failed trials, they don't change anything that we know about the risk and susceptibility of Alzheimer's disease or our ability to treat it today," says co-senior author and Alzheimer's disease specialist Sam Gandy. 

This is especially true because HHV-6A and HHV-7 are extremely common and often latent or asymptomatic: in North America, almost 90% of children have one of these viruses circulating in their blood by the time they're a few years old. "There are still a lot of unanswered questions around how we go from being able to detect it circulating in someone's blood to knowing whether it's active in a state that might be relevant to Alzheimer's disease," says Readhead.

Alzheimer's & Viruses: Specific and Testable

But even if questions remain, this research offers strong support for a long-controversial hypothesis that viruses might be involved in the development of Alzheimer's disease. "We didn't have a horse in this virus race whatsoever. It's the data that took us there. And now, not only is the viral hypothesis resurrected: it has specific testable pathways and networks and interactions that can be explored and reconciled with the rest of the work emerging in Alzheimer's," says Dudley. 

"All these Alzheimer's brains in these separate, major brain banks have previously unsuspected substantial populations of herpesvirus genomes and that deserves an explanation wherever it falls in the pathogenesis. It doesn't deserve to just be brushed away," says Gandy.

“The hypothesis that viruses play a part in brain disease is not new, but this is the first study to provide strong evidence based on unbiased approaches and large data sets that lends support to this line of inquiry,” said NIA Director Richard J. Hodes, M.D. “This research reinforces the complexity of Alzheimer’s disease, creates opportunities to explore Alzheimer’s more thoroughly, and highlights the importance of sharing data freely and widely with the research community.” 

Alzheimer’s disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills and, eventually, the ability to carry out simple tasks. More evidence is accumulating to indicate that this loss of cognitive functioning is a mix of many different disease processes in the brain, rather than just one, such as buildup of amyloid or tau proteins. Identifying links to viruses may help researchers learn more about the complicated biological interactions involved in Alzheimer’s, and potentially lead to new treatment strategies. 

The research group, which included experts from Icahn School of Medicine at Mount Sinai, New York City, and Arizona State University, Phoenix, originally set out to find whether drugs used to treat other diseases can be repurposed for treating Alzheimer’s. They designed their study to map and compare biological networks underlying Alzheimer’s disease. What they found is that Alzheimer’s biology is likely impacted by a complex constellation of viral and host genetic factors, adding that they identified specific testable pathways and biological networks.

Robust Findings

“The robust findings by the Mount Sinai team would not have been possible without the open science data resources created by the AMP-AD program–particularly the availability of raw genomic data,” said NIA Program Officer Suzana Petanceska, Ph.D., who leads the AMP-AD Target Discovery and Preclinical Validation Project. “This is a great example of the power of open science to accelerate discovery and replication research.” 

The researchers used multiple layers of genomic and proteomic data from several NIA-supported brain banks and cohort studies. They began their direct investigation of viral sequences using data from the Mount Sinai Brain Bank and were able to verify their initial observations using datasets from

• The Religious Orders Study
• The Memory and Aging Project and
• The Mayo Clinic Brain Bank.

They were then able to incorporate additional data from the Emory Alzheimer’s Disease Research Center to understand viral impacts on protein abundance. Through the application of sophisticated computational modeling the researchers made several key findings, including:

1. Human herpesvirus 6A and 7 were more abundant in Alzheimer’s disease samples than non-Alzheimer’s.
2. There are multiple points of overlap between virus-host interactions and genes associated with Alzheimer’s risk.
3. Multiple viruses impact the biology of Alzheimer’s disease across domains such as DNA, RNA and proteins.

No Evidence to Reassess Risk

Important roles for microbes and viruses in Alzheimer’s disease have been suggested and studied for decades, the authors noted. Since the 1980s, hundreds of reports have associated Alzheimer’s with bacteria and viruses. These studies combined suggest a viral contribution but have not explained how the connection works. 

While the current findings are more specific, they do not provide evidence to change how risk and susceptibility are assessed, nor the diagnosis and treatment of Alzheimer’s, the authors said. Rather, the research gives scientists reason to revisit the old pathogen hypothesis and will be the basis for further work that will test whether herpes virus activity is one of the causes of Alzheimer’s.

MORE INFORMATION:

• Note: This article describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process — each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research.
• About AMP-AD: The Accelerating Medicines Partnership is a joint venture among the National Institutes of Health, the Food and Drug Administration, 12 biopharmaceutical and life science companies and 13 non-profit organizations, managed by the Foundation for the NIH, to identify and validate promising biological targets of disease. AMP-AD is one of the four initiatives under the AMP umbrella; the other three are focused on type 2 diabetes (AMP-T2D), rheumatoid arthritis and systemic lupus erythematosus (AMP-RA/SLE) and Parkinson’s disease (AMP-PD). The AMP-AD knowledge portal already has over 1,300 total users. To learn more about the AMP-AD Target Discovery and Preclinical Validation Project, visit: https://www.nia.nih.gov/research/amp-ad.
• About the National Institute on Aging: The NIA leads the federal government effort conducting and supporting research on aging and the health and well-being of older people. The NIA is designated as the lead NIH institute for information on Alzheimer's disease. It provides information on age-related cognitive change and neurodegenerative disease, including participation in clinical studies, specifically on its Alzheimer's website.
• Reference: Readhead et al. Multiscale Analysis of Independent Alzheimer’s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Published in the journal "Neuron". 2018 Jun. 21. Doi: 10.1016/j.neuron.2018.05.023
  
  Neuron (@NeuroCellPress), published by Cell Press, is a bimonthly journal that has established itself as one of the most influential and relied upon journals in the field of neuroscience and one of the premier intellectual forums of the neuroscience community. It publishes interdisciplinary articles that integrate biophysical, cellular, developmental, and molecular approaches with a systems approach to sensory, motor, and higher-order cognitive functions. Visit: http://www.cell.com/neuron. To receive Cell Press media alerts, contact press@cell.com.

SOURCES:

• Cell Press
• SWNS TV
• National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov. NIH…Turning Discovery Into Health®

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November is Alzheimer's Awareness Month

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The Alzheimer's Association was founded in 1980. It has been the leader in making the fight against Alzheimer’s disease a national priority, Every November this organization makes an extra effort to enlighten the general public about Alzheimer's disease by having National Alzheimer’s Disease Awareness Month.
See President Obama's proclamation of National Alzheimer's Disease Awareness Month

President Ronald Reagan helped to launch a national campaign against Alzheimer’s disease in 1983 after he designated a National Alzheimer’s Disease Week in 1982. He called members of the Alzheimer's Association to the White House for the signing of a proclamation declaring National Alzheimer’s Disease Month.

The founder of the Alzheimer’s Association was Jerome Stone. He led a group of family caregivers, Association volunteers and staff in the effort to bring attention to the cause on Capitol Hill. That advocacy effort continues even stronger today with Association public policy staff and volunteers leading the call for increased government funding for critical Alzheimer research and support programs. Anyone can become an Alzheimer's disease advocate.

November is National Alzheimer's Disease Awareness Month and National Family Caregivers Month
According to the Alzheimer’s Association 2017
Alzheimer’s Disease Facts and Figures report, there are more than 5.3 million people are living with Alzheimer’s and over 10 million family caregivers. This November, during National Alzheimer’s Disease Awareness Month and National Family Caregivers Month, the Alzheimer’s Association

What are you doing to find out all you can about this mind robbing disease and related dementias?
Visit this blog often to find out the latest news.
Here is what the president had to say
A Proclamation by the President of the United States of America
During National Alzheimer's Disease Awareness Month, we recognize the dignity and courage of the men and women living with Alzheimer's disease. We also honor the devoted family members and caretakers who bring them love and comfort, and we underscore our dedication to finding a cure for this tragic disease
...read the whole proclamation from 2011
Become an Alzheimer's advocate

Sleep clears Alzheimers

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The Dementia Caregiver's Little Book of Hope [Kindle Edition

National Institutes of Health

Beta-amyloid (also known as "plaque") is the main suspect behind Alzheimer's. Sleep cleared it TWICE as quickly as normal in the lab. Find out how sleep doubles the clearance of this dangerous Alzheimer's molecule. 

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A mouse study suggests that sleep helps restore the brain by flushing out toxins that build up during waking hours. The results point to a potential new role for sleep in health and disease.

Scientists watched dye flow through the glymphatic system, a brain "plumbing" system, of a mouse when it was asleep (left) and then, later, when it was awake (right). More dye flowed into the brain during sleep. Results from this study suggest the brain may flush out toxic molecules associated with neurodegenerative disorders during sleep. Courtesy of Nedergaard Lab, University of Rochester Medical Center.

Scientists and philosophers have long wondered why people sleep and how it affects the brain. Sleep is important for storing memories. It also has a restorative function. Lack of sleep impairs reasoning, problem-solving, and attention to detail, among other effects. However, the mechanisms behind these sleep benefits have been unknown.

Dr. Maiken Nedergaard and her colleagues at the University of Rochester Medical Center recently discovered a system that drains waste products from the brain. Cerebrospinal fluid, a clear liquid surrounding the brain and spinal cord, moves through the brain along a series of channels that surround blood vessels. The system is managed by the brain’s glial cells, and so the researchers called it the glymphatic system.

The scientists also reported that the glymphatic system can help remove a toxic protein called beta-amyloid from brain tissue. Beta-amyloid is renowned for accumulating in the brains of patients with Alzheimer's disease. Other research has shown that brain levels of beta-amyloid decrease during sleep. In their new study, the team tested the idea that sleep might affect beta-amyloid clearance by regulating the glymphatic system. The work was funded by NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

The researchers first injected dye into the cerebrospinal fluid of mice and monitored electrical brain activity as they tracked the dye flow through the animals’ brains. As reported in the October 18, 2013, edition of Science, the dye barely flowed when the mice were awake. In contrast, when the mice were unconscious—asleep or anesthetized—it flowed rapidly.

Changes in the way fluid moves through the brain between conscious and unconscious states may reflect differences in the space available for movement. To test the idea, the team used a method that measures the volume of the space outside brain cells. They found that this “extracellular” volume increased by 60% in the brain’s cortex when the mice were asleep or anesthetized.

The researchers next injected mice with labeled beta-amyloid and measured how long it lasted in their brains when they were asleep and awake. Beta-amyloid disappeared twice as quickly in the brains of mice that were asleep.

Glial cells control flow through the glymphatic system by shrinking and swelling. The hormone noradrenaline, which increases alertness, is known to cause cells to swell. The researchers thus tested whether the hormone might affect the glymphatic system. Treating mice with drugs that block noradrenaline induced a sleep-like state and increased brain fluid flow and extracellular brain volume. This result suggests a molecular connection between the sleep-wake cycle and the brain’s cleaning system.

The study raises the possibility that certain neurological disorders might be prevented or treated by manipulating the glymphatic system. “These findings have significant implications for treating ‘dirty brain’ diseases like Alzheimer’s,” Nedergaard says. “Understanding precisely how and when the brain activates the glymphatic system and clears waste is a critical first step in efforts to potentially modulate this system and make it work more efficiently.”

Why Scientists Are Still Puzzled by Alzheimer's

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The Dementia Caregiver's Little Book of Hope [Kindle Edition 

Preventing memory loss and restoring it once it's gone is the holy grail of brain science. In the United States alone, an estimated 5.4 million people are living with Alzheimer's disease. 

But recently, unexpected and disappointing findings have underlined just how difficult it is to develop therapies for cognitive decline.In November, Eli Lilly announced that its Alzheimer’s drug solanezumab failed to show a significant benefit for people with mild forms of Alzheimer's. “The outcome was not what we hoped for, and that is disappointing for the millions of people waiting for a potential disease-modifying treatment for Alzheimer’s disease,” Dr. Eric Siemers, medical director of the Alzheimer’s Disease Team at Lilly said during a teleconference.

And in another study of a potential treatment, released Wednesday, researchers found that deep brain stimulation didn't improve memory—in fact, it worsened it. "That was the most surprising thing," says study author Joshua Jacobs, an assistant professor of biomedical engineering at Columbia's Fu Foundation School of Engineering and Applied Science. "We found a small but statistically very robust decrease in memory, which is not what we had hoped for."

Deep brain stimulation is a procedure where electrodes are implanted into a person's brain, and an electrical current stimulates those areas. Prior, smaller studies have had promising findings but in the new study, the researchers found the people performed worse on recall tasks when the stimulation was turned on. The effects were temporary, and the procedure had no lasting impact on memory.

Jacobs says it's possible the procedure could work with refinement. One of his co-authors recently found improvements in people's verbal memory with more varied stimulation.

But why is it so difficult to create effective therapies for memory?

"Memory is one of the most complex processes the brain carries out," says Jacobs. "Memory is part of all aspects of the conscious experience. To understand and improve a process that involves the whole brain or a lot of the brain is a big challenge."

Let's say you were asked to remember your birthday last year. Different parts of the brain will contribute to the recall of where you were, what was happening, and how you were feeling at the time. It's a complex feat and the various processes at play can be difficult to untangle.

"Memory isn't really an ability, it's really a collection of different abilities," says Charan Ranganath , a professor at UC Davis Center for Neuroscience who has also studied brain stimulation for memory. "I could teach you a good mnemonic trick to help remember names that go with faces, but that won't help you remember your upcoming doctor appointment or the plot of a complicated movie." Ranganath was not involved in the recent study.

Memory is also very hard to regain after it's lost. If a person develops memory problems from a stroke or Alzheimer's disease, the damage has been done and the options are few. That's why prevention has become a target. But what's done in a lab doesn't always apply to how people make memories in the real world. " One of our biggest challenges is translate what we know about precise processes in the brain into tests and biomarkers that are sensitive to memory disorders," says Ranganath.

Yet while there's a lot unknown about how to treat ailments of the brain, there's a lot we do know too. The link between the mind and body has never been more apparent: doctors now know that type 2 diabetes significantly increases a person's risk for Alzheimer's, and depression also takes a toll on memory. Preventing or treating these diseases may cut back on the risk for memory loss over time. " The difficult part is that people don't necessarily want to do what is needed to improve your memory," says Ranganath. "I'm a great example—I'm out of shape, chronically stressed out, and I don't get enough sleep!"

But scientists continue to explore possibilities. Some attempts, like brain games, may not work as well as intended, but others like improving diet, exercising more, or even improvements in brain stimulation, may be successful down the line.

Time

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Detecting Alzheimer's disease earlier

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Eurekalert

LOUISVILLE, Ky. - Unique graphic characters called Greebles may prove to be valuable tools in detecting signs of Alzheimer's disease decades before symptoms become apparent.

In an article published online last week in Journal of Alzheimer's Disease, Emily Mason, Ph.D., a postdoctoral associate in the Department of Neurological Surgery at the University of Louisville, reported research showing that cognitively normal people who have a genetic predisposition for Alzheimer's disease (AD) have more difficulty distinguishing among novel figures called Greebles than individuals without genetic predisposition.

Alzheimer's disease (AD) is a progressive, irreversible neurodegenerative disease characterized by declining memory, cognition and behavior. AD is the most prevalent form of dementia, affecting an estimated 5.5 million individuals in the United States and accounting for 60 to 80 percent of dementia cases. The ability to detect the disease earlier may allow researchers to develop treatments to combat the disease.

"Right now, by the time we can detect the disease, it would be very difficult to restore function because so much damage has been done to the brain," Mason said. "We want to be able to look at really early, really subtle changes that are going on in the brain. One way we can do that is with cognitive testing that is directed at a very specific area of the brain."

AD is characterized by the presence of beta amyloid plaques and tau neurofibrillary tangles in the brain. Tau tangles predictably develop first in the perirhinal and entorhinal cortices of the brain, areas that play a role in visual recognition and memory. Mason and her colleagues developed cognitive tests designed to detect subtle deficiencies in these cognitive functions. They hoped to determine whether changes in these functions would indicate the presence of tau tangles before they could be detected through imaging or general cognitive testing.

Working in her previous position at Vanderbilt University, Mason identified test subjects age 40-60 who were considered at-risk for AD due to having at least one biological parent diagnosed with the disease. She also tested a control group of individuals in the same age range whose immediate family history did not include AD.

The subjects completed a series of "odd-man-out" tasks in which they were shown sets of four images depicting real-world objects, human faces, scenes and Greebles in which one image was slightly different than the other three. The subjects were asked to identify the image that was different.

The at-risk and control groups performed at similar levels for the objects, faces and scenes. For the Greebles, however, the at-risk group scored lower in their ability to identify differences in the images. Individuals in the at-risk group correctly identified the distinct Greeble 78 percent of the time, whereas the control group correctly identified the odd Greeble 87 percent of the time.

"Most people have never seen a Greeble and Greebles are highly similar, so they are by far the toughest objects to differentiate," Mason said. "What we found is that using this task, we were able to find a significant difference between the at-risk group and the control group. Both groups did get better with practice, but the at-risk group lagged behind the control group throughout the process."

Mason would like to see further research to determine whether the individuals who performed poorly on the test actually developed AD in the future.

"The best thing we could do is have people take this test in their 40s and 50s, and track them for the next 10 or 20 years to see who eventually develops the disease and who doesn't," Mason said.

In recent years, a great deal of research has focused on identifying early biomarkers of Alzheimer's disease. However, not everyone who has an individual biomarker ultimately develops the disease. Brandon Ally, Ph.D., assistant professor of neurological surgery at UofL and senior author of the publication, said the tests with Greebles can provide a cost-effective way to identify individuals who may be in the early stages of AD, as well as a tool for following those individuals over time.

"We are not proposing that the identification of novel objects such as Greebles is a definitive marker of the disease, but when paired with some of the novel biomarkers and a solid clinical history, it may improve our diagnostic acumen in early high-risk individuals," Ally said. "As prevention methods, vaccines or disease modifying drugs become available, markers like novel object detection may help to identify the high priority candidates."

Robert P. Friedland, M.D., professor and Mason and Mary Rudd Endowed Chair in Neurology at UofL, has studied clinical and biological issues in Alzheimer's disease and related disorders for 35 years. He believes that early detection will enhance the ability of patients and physicians to employ lifestyle and therapeutic interventions.

"This work shows that the effects of Alzheimer's disease on cognition can be measured decades before the onset of dementia," Friedland said. "The fact that the disease takes so long to develop provides us with an opportunity to slow its progression through attention to the many factors that are linked to the disease, such as a sedentary lifestyle, a high fat diet, obesity, head injury, smoking, and a lack of mental and social engagement."

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The article, "Family history of Alzheimer's disease is associated with impaired perceptual discrimination of novel objects," will appear in the Journal of Alzheimer's Disease, Volume 57, Issue 2.

ANSWER: Greeble No. 4 is different.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Overuse of antipsychotropic meda affect those with Alzheimer's disease

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neuroscience news

Research lead is related to the use of psychotropic medications in Alzheimer’s patients. I should note that strong cautions have already been issued with respect to the use of these medications in the elderly (e.g. https://www.mind.uci.edu/alzheimers-disease/articles-of-interest/medications-to-avoid-for-patients/). As a practical matter, however, at present agitated and aggressive behaviors are considered a common symptom of advanced Alzheimer’s and therefore the use of these drugs as chemical restraints is common even by the most conservative physicians. Furthermore, as the medical profession is very diverse many physicians have not updated their practice and are far from cautious in prescribing these medications to the elderly. Indeed, chemical restraints are the norm in nursing home practice, so it is my belief that psychotropic medications are ubiquitous in nursing homes.

A family member is an active medical professional (a physician assistant who works as a front-line health care provider in a family practice office in rural America), so I have some insight into how a conservative medical practitioner will behave. I have observed two things: first, when a symptom is in the list of potential symptoms for a disease that has been diagnosed in the patient, there is a strong presumption that the symptom is caused by the disease. Second, when a symptom is a side effect of a medication (particularly one prescribed by another doctor), there is a presumption that the need for the medication outweighs the side effect.

A combination of close familiarity with my mother’s symptoms/behavior on and off a variety of drugs and my knowledge of the ubiquitous bank gaming of regulatory controls in financial markets leads me to wonder whether the drug companies aren’t playing the same kind of game. In particular the addition of “behavioral and psychological symptoms of dementia” (BPSD) to the criteria for the diagnosis of late-stage Alzheimer’s is as far as I can tell of very recent vintage. (I believe they were introduced with the DSM-5 in 2013.) BPSD are symptoms treated by psychotropic medications. These same medications are also commonly used to treat mild sleep and anxiety disorders in the general population.

The problem with all the psychotropic medications is that they are used to treat the same behaviors that they can also cause as side effects, including irritability, anxiety, “disinhibition” which maps into a willingness to hit out at or behave abusively to others, aggressiveness, and self-harm. In sufficiently high doses, however, the patient is heavily sedated and they are very effective chemical restraints.

My suspicion is that the introduction of BPSD into the definition of common symptoms of Alzheimer’s has developed as a result of the ubiquitous use of psychotropic medications in this population. That is, as far as I can tell the studies that have found BPSD to be common in Alzheimer’s are population-based studies that did not control for the use of medications that have as side effects BPS behaviors. Successfully bringing BPSD into the clinical definition of Alzheimer’s is hugely profitable for the drug companies that now have physician’s biases – to attribute symptoms to the disease that has already been diagnosed, rather than to the drug that may cause it as a side effect – working on their side.

In short, what I would really like to see is a careful statistician’s review of the studies that find that BPSD are common symptoms of Alzheimer’s and an analysis of whether sufficient controls for the use of medicines that have as side effects the same symptoms have been implemented. (With psychotropic medications, the length of use is an important factor because they build up in the system. Thus long-term use has different effects from short-term use. Long-term prescriptions are not a good proxy for long-term use, since refill/renewal of shorter term prescriptions is common practice.)

Can Stabilizing Amyloid Stop Alzheimer's?

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Alzheimer's and Dementia Weekly

BREAKTHROUGH: Never-before-seen images have exposed a missing link in the early-Alzheimer's cascade. Taken by the world's largest synchrotron, they imply new drugs may do better stabilizing amyloid than eliminating it. Learn more about this course-changing discovery. 

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Researchers at Lund University in Sweden have used the MAX IV synchrotron in Lund - the strongest of its kind in the world - to produce images that predate the formation of toxic clumps of beta-amyloid, the protein believed to be at the root of Alzheimer's disease. 

The unique images appear to contradict a previously unchallenged consensus. Instead of attempting to eliminate beta-amyloid, or so-called plaques, the researchers now suggest stabilizing the protein. 

It is a long-held belief in the scientific community that the beta-amyloid plaques appear almost instantaneously. Hence the term "popcorn plaques". The infrared spectroscopy images, however, revealed something entirely different. 


The researchers could now see structural, molecular changes in the brain. 

"No one has used this method to look at Alzheimer's development before. The images tell us that the progression is slower than we thought and that there are steps in the development of Alzheimer's disease that we know little about. This, of course, sparked our curiosity," says Gunnar Gouras, professor in experimental neurology at Lund University and senior author of the study. 

What was happening at this previously unknown phase? Through biochemical identification the first author of the study, Oxana Klementieva, was able to look closer at these early brain changes. 

The results revealed another discovery. Namely, that the beta-amyloid did not appear as a single peptide, a widely held belief in the field, but as a unit of four peptides sticking together, a tetramer. 

This breakthrough offers a new hypothesis to the cause of the disease. The abnormal separation of these four peptides could be the start of the beta-amyloid aggregation that later turns into plaques. 

"This is very, very exciting. In another amyloid disease, transthyretin amyloidosis, the breaking up of the tetramer has been identified as key in disease development. For this disease, there is already a drug in the clinic that stabilizes the tetramers, consequently slowing down disease progression. We hope that stabilizing beta-amyloid in a similar fashion may be the way forward in developing future therapies" says Gunnar Gouras. 

The discovery could therefore alter the direction of therapy development for the disease. The aim of most clinical trials today is to eliminate plaques. 

Researchers at Lund University will now try to understand the interaction patterns of beta-amyloid preceding the aggregation process. Finding the antidote to whatever breaks the beta-amyloid protein apart could open doors towards a major shift in­ the development of therapies for Alzheimer's disease.