Can scientists find the ‘holy grail’ of Alzheimer’s research?
- Alzheimer's is a neurodegenerative disease that is estimated to affect twice as many Americans by 2050, making it a troubling eventuality for many young adults.
- There's currently no cure for Alzheimer's, but clinical trials of immunotherapy approaches show promise.
- Immunotherapies may also alleviate the psychotic symptoms of Alzheimer's, like agitation, aggression, and paranoia.
It can be hard to conceptualize the total damage caused by Alzheimer's. The neurodegenerative disease is a leading cause of death in the U.S., killing more than 100,000 people each year. And as Alzheimer's progresses in the brain it not only erodes memory but also causes troubling symptoms like agitation, paranoia, and aggression.
These burdens fall not only on patients but also on their loved ones, doctors, and caregivers. Economically, the cost of caring for Alzheimer's patients hit an estimated $305 billion in 2020, according to a report from the Alzheimer's Association. And that figure doesn't include an estimated $244 billion in unpaid caregiving provided by family and friends.
The number of Alzheimer's patients in the U.S. is expected to double by 2050, affecting about 14 million people. That's one reason why hospitals and health professionals are already working to bolster how they care for the elderly and Alzheimer's patients. It takes 15 years to develop new treatments, so today's research needs adequate funding.
"Caring for our older adults is a big responsibility, one that we take great pride in," said Michael Dowling, president and CEO of Northwell Health. "Our aging population will face health issues, including and especially Alzheimer's, that will require the right care at the right time. That's why we have increased our services, including at Glen Cove Hospital, and research at the Feinstein Institutes for Medical Research."
... the real suffering comes from the changes that happen in the personality...
What causes Alzheimer’s disease?
While the costs of Alzheimer's are clear, its exact causes remain frustratingly mysterious. Currently, there's no cure for the disease, nor treatments that stop its progression.
"Alzheimer's is this brain problem, and everyone sort of knows what's probably causing the problem, but nobody's been able to do anything about it," said Dr. Jeremy Koppel, a geriatric psychiatrist and co-director of the Litwin-Zucker Alzheimer Research Center.
But in recent decades, researchers have zeroed in on likely contributors to the disease. The brains of Alzheimer's patients reliably show two abnormalities: build-ups of proteins called abnormal tau and beta-amyloid. As these proteins accumulate in the brain, they disrupt healthy communication between neurons. Over time, neurons get injured and die, and brain tissue shrinks.
Still, it's unclear exactly how these proteins, or other factors such as inflammation, may drive Alzheimer's.
"We are dealing with very complicated components," said Dr. Philippe Marambaud, a professor at the Feinstein Institutes and co-director of the Litwin-Zucker Alzheimer Research Center. "The actual culprit is not clearly defined. We know there are three possible culprits [tau, beta-amyloid, inflammation]. They're working in concert, or maybe in isolation. We don't know precisely."
Many Alzheimer's researchers have spent years developing therapies that target beta-amyloid, which can accumulate to form plaques in the brain. The Alzheimer's Association writes:
"According to the amyloid hypothesis, these stages of beta-amyloid aggregation disrupt cell-to-cell communication and activate immune cells. These immune cells trigger inflammation. Ultimately, the brain cells are destroyed."
Unfortunately, clinical trials of therapies that target beta-amyloid haven't been effective in treating Alzheimer's.
Anti-tau immunotherapies: The holy grail of Alzheimer’s?
In brains with Alzheimer's disease, tau proteins lose their structure and form neurofibrillary tangles that block communication between synapses.
Credit: Adobe Stock
At the Feinstein Institutes, Dr. Marambaud and his colleagues have been focusing on the lesser-explored Alzheimer's component: abnormal tau.
In healthy brains, tau plays several important functions, including stabilizing internal microtubules in neurons. But in the brains of Alzheimer's patients, a process called phosphorylation changes the structure of tau proteins. This blocks synaptic communication.
Dr. Marambaud said there are good reasons to think anti-tau therapies may effectively treat Alzheimer's.
"The main argument around why [anti-tau therapies] could be more beneficial is that we've known for a very long time that tau pathology in the brain of the Alzheimer's patient correlates much better with the disease progression, and the loss of neuronal material in the brain," compared to beta-amyloid, Dr. Marambaud said.
"The second strong argument is that there are inherited dementias, called tauopathies, which are caused by mutations in the gene coding for the tau protein. So, there is a direct genetic link between dementia and tau pathology."
To better understand how this protein interacts with Alzheimer's, Dr. Marambaud and his colleagues have been developing immunotherapies that target abnormal tau.
Immunotherapies, such as vaccines, typically target infectious diseases. But it's also possible to use the body's immune system to prevent or treat some non-infectious diseases. Scientists have recently succeeded in treating certain forms of cancer with immunotherapies, for example.
"We have developed a series of monoclonal antibodies, which are basically the therapeutics that are required when you want to do immunotherapy," Dr. Marambaud said.
Currently, Feinstein Institutes researchers are conducting promising ongoing clinical trials with anti-tau antibodies, some of which are in phase III trials under the Food and Drug Administration. Patients receive these therapies intravenously over several hours and would undergo multiple rounds of treatment. It's similar to chemotherapy.
In the short term, it's more likely that anti-tau therapies would help to stabilize Alzheimer's, not cure it.
"Just stabilization of the disease's progression will save a huge societal, but also financial, burden," Dr. Marambaud said. "As research progresses, we would improve upon these stabilization approaches to make them more and more efficacious."
Even if anti-tau therapies don't prove to be the holy grail of Alzheimer's treatments, they could potentially alleviate severe behavioral symptoms of the disease, and potentially illuminate some of the mechanisms behind psychosis.
Alzheimer’s and psychosis
Credit: Getty Images
When most people think of Alzheimer's, they tend to focus on the erosion of memory. But the darkest effects of the disease are often psychotic symptoms like agitation, aggression and paranoia, according to Dr. Koppel, who, in addition to researching Alzheimer's, spent decades treating Alzheimer's patients as a clinician.
"My research focus comes out of 20 years of sitting with Alzheimer's families and listening to what the primary issue is," said Dr. Koppel. "It's never memory. It starts out with memory as a diagnostic issue. But the real suffering comes from the changes that happen in the personality and the belief system that make Alzheimer's patients" ostracized or even become violent toward their loved ones.
At the Feinstein Institutes, Dr. Koppel's research focuses on alleviating Alzheimer's-related psychotic symptoms through anti-tau immunotherapies.
"It's our hypothesis that abnormal tau proteins in the brain somehow, downstream, impact the way that people think," Dr. Koppel said. "And the impact that it has is this paranoid, agitated, psychotic phenotype."
Supporting this hypothesis is research on chronic traumatic encephalopathy (CTE), a degenerative disease that involves the accumulation of abnormal tau. CTE, common among professional football players, also causes psychotic symptoms like agitation, aggression and paranoia.
What's more, research shows that as Alzheimer's patients accumulate more abnormal tau in their brains, as measured through cerebrospinal fluid, they exhibit more psychotic symptoms, and are more likely to die sooner than patients with less abnormal tau.
Given these strong connections between psychosis and abnormal tau, Dr. Koppel and his colleagues hope that anti-tau immunotherapies will alleviate psychosis in Alzheimer's patients, who currently lack safe and effective treatment options and are often given medication that is meant to alleviate psychosis in people with schizophrenia.
"We are giving medications to Alzheimer's patients that hasten their cognitive decline and lead to bad outcomes, like stroke and sudden death," Dr. Koppel said. "Nonetheless, the schizophrenia medications do treat some of the psychotic symptoms and aggressive behavior related to Alzheimer's disease, and for many families this is crucial. We just don't have many options, and we desperately need more."
Beyond treating Alzheimer's patients, anti-tau immunotherapies may shed light on other mental illnesses.
"Alzheimer's may give us a window into what happens in the brain that makes people psychotic," Dr. Koppel said. "Once you have a biologic treatment for psychosis that gets at an underlying pathophysiology, believe me, you could look at schizophrenia in new ways. Maybe it's not going to be tau, but it may be a paradigm for treating mental illness."
The future of Alzheimer’s treatments
Dr. Marambaud said the long-term goal of anti-tau immunotherapies is to prevent Alzheimer's. But that's currently impossible because scientists lack the biomarkers and diagnostic tools needed to detect the disease before cognitive symptoms appear. It could take decades before prevention becomes possible, if it ever does.
In the short term, stabilizing Alzheimer's is a more realistic goal.
"Our hope is that the treatments will be aggressive enough so that we can at least stabilize the disease in patients identified to be already affected by dementia, with cognitive tests that can be done by the clinicians," Dr. Marambaud said. "And even better, maybe reduce the cognitive impairments."
Dr. Marambaud said he encourages the public not to lose faith.
"Be patient. It's a very complicated disease," he said. "A lot of labs are really committed to making a difference. Congress has also realized that this is a huge priority. In the past five years, [National Institutes of Health] funding has increased tremendously. So the scientific field is working very hard. The politicians are behind us in funding this research. And it's a complicated disease. But we will make a difference in the years to come."
In the meantime, the Alzheimer's Association notes that physical activity and a healthy diet can reduce the chances of developing Alzheimer's, though more large-scale studies are needed to better understand how these factors interact with the disease.
"Many of these lifestyle changes have been shown to lower the risk of other diseases, like heart disease and diabetes, which have been linked to Alzheimer's," the association wrote. "With few drawbacks and plenty of known benefits, healthy lifestyle choices can improve your health and possibly protect your brain."
Elephants dilate their nostrils to create more space in their trunks, allowing them to store up to 5.5 liters (1.45 gallons) of water, according to their new study.
They can also suck up three liters (0.79 gallons) per second—a speed 30 times faster than a human sneeze (150 meters per second/330 mph), the researchers found.
The researchers wanted to better understand the physics of how elephants use their trunks to move and manipulate air, water, food, and other objects. They also wanted to learn if the mechanics could inspire the creation of more efficient robots that use air motion to hold and move things.
Photo by David Clode on Unsplash
While octopuses use jets of water to propel themselves and archer fish shoot water above the surface to catch insects, elephants are the only animals able to use suction both on land and underwater.
"An elephant eats about 400 pounds of food a day, but very little is known about how they use their trunks to pick up lightweight food and water for 18 hours, every day," says lead author Andrew Schulz, a mechanical engineering PhD student at the Georgia Institute of Technology. "It turns out their trunks act like suitcases, capable of expanding when necessary."
Sucking up tortilla chips without breaking them
Schulz and his colleagues worked with veterinarians at Zoo Atlanta, studying elephants as they ate various foods. For large rutabaga cubes, for example, the animal grabbed and collected them. It sucked up smaller cubes and made a loud vacuuming sound, like the sound of a person slurping noodles, before transferring the vegetables to its mouth.
To learn more about suction, the researchers gave elephants a tortilla chip and measured the applied force. Sometimes the animal pressed down on the chip and breathed in, suspending the chip on the tip of its trunk without breaking it, similar to a person inhaling a piece of paper onto their mouth. Other times the elephant applied suction from a distance, drawing the chip to the edge of its trunk.
Elephants inhale at speeds comparable to Japan's 300 mph bullet trains.
"An elephant uses its trunk like a Swiss Army knife," says David Hu, Schulz's advisor and a professor in Georgia Tech's School of Mechanical Engineering. "It can detect scents and grab things. Other times it blows objects away like a leaf blower or sniffs them in like a vacuum."
By watching elephants inhale liquid from an aquarium, the team was able to time the durations and measure volume. In just 1.5 seconds, the trunk sucked up 3.7 liters (just shy of 1 gallon), the equivalent of 20 toilets flushing simultaneously.
Soft robots and elephant conservation
The researchers used an ultrasonic probe to take trunk wall measurements and see how the trunk's inner muscles work. By contracting those muscles, the animal dilates its nostrils up to 30%. This decreases the thickness of the walls and expands nasal volume by 64%.
"At first it didn't make sense: an elephant's nasal passage is relatively small and it was inhaling more water than it should," Schulz says. "It wasn't until we saw the ultrasonographic images and watched the nostrils expand that we realized how they did it. Air makes the walls open, and the animal can store far more water than we originally estimated."
Based on the pressures applied, Schulz and the team suggest that elephants inhale at speeds comparable to Japan's 300-mph bullet trains.
Schulz says these unique characteristics have applications in soft robotics and conservation efforts.
"By investigating the mechanics and physics behind trunk muscle movements, we can apply the physical mechanisms—combinations of suction and grasping—to find new ways to build robots," Schulz says.
"In the meantime, the African elephant is now listed as endangered because of poaching and loss of habitat. Its trunk makes it a unique species to study. By learning more about them, we can learn how to better conserve elephants in the wild."
The paper appears in the Journal of the Royal Society Interface. The US Army Research Laboratory and the US Army Research Office 294 Mechanical Sciences Division, Complex Dynamics and Systems Program, funded the work. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the view of the sponsoring agency.
Source: Georgia Tech
Original Study DOI: 10.1098/rsif.2021.0215
Reprinted with permission of Futurity. Read the original article.
As he described it, “In my mind's eye I saw many, many things: children that I hadn't even had yet, friends that I had never seen but are now my friends. The thing that really stuck in my mind was playing an instrument". Then Tony landed on his head and lost consciousness.
When he came to at the hospital, he felt like a different person and didn't want to return to his previous life. Over the following weeks, the images kept flashing back into his mind. He felt that he was “being shown something" and that the images represented his future.
Later, Tony saw a picture of a saxophone and recognized it as the instrument he'd seen himself playing. He used his compensation money from the accident to buy one. Now, Tony Kofi is one of the UK's most successful jazz musicians, having won the BBC Jazz awards twice, in 2005 and 2008.
Though Tony's belief that he saw into his future is uncommon, it's by no means uncommon for people to report witnessing multiple scenes from their past during split-second emergency situations. After all, this is where the phrase “my life flashed before my eyes" comes from.
But what explains this phenomenon? Psychologists have proposed a number of explanations, but I'd argue the key to understanding Tony's experience lies in a different interpretation of time itself.
When life flashes before our eyes
The experience of life flashing before one's eyes has been reported for well over a century. In 1892, a Swiss geologist named Albert Heim fell from a precipice while mountain climbing. In his account of the fall, he wrote is was “as if on a distant stage, my whole past life [was] playing itself out in numerous scenes".
More recently, in July 2005, a young woman called Gill Hicks was sitting near one of the bombs that exploded on the London Underground. In the minutes after the accident, she hovered on the brink of death where, as she describes it: “my life was flashing before my eyes, flickering through every scene, every happy and sad moment, everything I have ever done, said, experienced".
In some cases, people don't see a review of their whole lives, but a series of past experiences and events that have special significance to them.
Explaining life reviews
Perhaps surprisingly, given how common it is, the “life review experience" has been studied very little. A handful of theories have been put forward, but they're understandably tentative and rather vague.
For example, a group of Israeli researchers suggested in 2017 that our life events may exist as a continuum in our minds, and may come to the forefront in extreme conditions of psychological and physiological stress.
Another theory is that, when we're close to death, our memories suddenly “unload" themselves, like the contents of a skip being dumped. This could be related to “cortical disinhibition" – a breaking down of the normal regulatory processes of the brain – in highly stressful or dangerous situations, causing a “cascade" of mental impressions.
But the life review is usually reported as a serene and ordered experience, completely unlike the kind of chaotic cascade of experiences associated with cortical disinhibition. And none of these theories explain how it's possible for such a vast amount of information – in many cases, all the events of a person's life – to manifest themselves in a period of a few seconds, and often far less.
Thinking in 'spatial' time
An alternative explanation is to think of time in a “spatial" sense. Our commonsense view of time is as an arrow that moves from the past through the present towards the future, in which we only have direct access to the present. But modern physics has cast doubt on this simple linear view of time.
Indeed, since Einstein's theory of relativity, some physicists have adopted a “spatial" view of time. They argue we live in a static “block universe" in which time is spread out in a kind of panorama where the past, the present and the future co-exist simultaneously.
The modern physicist Carlo Rovelli – author of the best-selling The Order of Time – also holds the view that linear time doesn't exist as a universal fact. This idea reflects the view of the philosopher Immanuel Kant, who argued that time is not an objectively real phenomenon, but a construct of the human mind.
This could explain why some people are able to review the events of their whole lives in an instant. A good deal of previous research – including my own – has suggested that our normal perception of time is simply a product of our normal state of consciousness.
In many altered states of consciousness, time slows down so dramatically that seconds seem to stretch out into minutes. This is a common feature of emergency situations, as well as states of deep meditation, experiences on psychedelic drugs and when athletes are “in the zone".
The limits of understanding
But what about Tony Kofi's apparent visions of his future? Did he really glimpse scenes from his future life? Did he see himself playing the saxophone because somehow his future as a musician was already established?
There are obviously some mundane interpretations of Tony's experience. Perhaps, for instance, he became a saxophone player simply because he saw himself playing it in his vision. But I don't think it's impossible that Tony did glimpse future events.
If time really does exist in a spatial sense – and if it's true that time is a construct of the human mind – then perhaps in some way future events may already be present, just as past events are still present.
Admittedly, this is very difficult to make sense of. But why should everything make sense to us? As I have suggested in a recent book, there must be some aspects of reality that are beyond our comprehension. After all, we're just animals, with a limited awareness of reality. And perhaps more than any other phenomenon, this is especially true of time.
Steve Taylor, Senior Lecturer in Psychology, Leeds Beckett University
This article is republished from The Conversation under a Creative Commons license. Read the original article.
