Can scientists find the ‘holy grail’ of Alzheimer’s research?
Clinical trials at the Feinstein Institutes for Medical Research focus on stabilizing cognitive loss and alleviating the psychotic symptoms that change our loved ones.
Stephen Johnson is a St. Louis-based writer whose work has been published by outlets including PBS Digital Studios, HuffPost, MSN, U.S. News & World Report, Eleven Magazine and The Missourian.
- 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."
This storm rained electrons, shifted energy from the sun's rays to the magnetosphere, and went unnoticed for a long time.
- An international team of scientists has confirmed the existence of a "space hurricane" seven years ago.
- The storm formed in the magnetosphere above the North magnetic pole.
- The storm posed to risk to life on Earth, though it might have interfered with some electronics.
What do you call that kind of storm when it forms over the Arctic ocean?<iframe width="730" height="430" src="https://www.youtube.com/embed/8GqnzBJkWcw" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture" allowfullscreen></iframe><p> Many objects in space, like Earth, the Sun, most of the planets, and even some large moons, have magnetic fields. The area around these objects which is affected by these fields is known as the magnetosphere.</p><p>For us Earthlings, the magnetosphere is what protects us from the most intense cosmic radiation and keeps the solar wind from affecting our atmosphere. When charged particles interact with it, we see the aurora. Its fluctuations lead to changes in what is known as "space weather," which can impact electronics. </p><p>This "space hurricane," as the scientists are calling it, was formed by the interactions between Earth's magnetosphere and the <a href="https://en.wikipedia.org/wiki/Interplanetary_magnetic_field" target="_blank" rel="noopener noreferrer">interplanetary magnetic field,</a> the part of the sun's magnetosphere that goes out into the solar system. It took on the familiar shape of a cyclone as it followed magnetic fields. For example, the study's authors note that the numerous arms traced out the "footprints of the reconnected magnetic field lines." It rotated counter-clockwise with a speed of nearly 7,000 feet per second. The eye, of course, was still and <a href="https://www.sciencealert.com/for-the-first-time-a-plasma-hurricane-has-been-detected-in-space" target="_blank" rel="noopener noreferrer">calm</a>.</p><p>The storm, which was invisible to the naked eye, rained electrons and shifted energy from space into the ionosphere. It seems as though such a thing can only form under calm situations when large amounts of energy are moving between the solar wind and the upper <a href="https://www.reading.ac.uk/news-and-events/releases/PR854520.aspx" target="_blank">atmosphere</a>. These conditions were modeled by the scientists using 3-D <a href="https://www.nature.com/articles/s41467-021-21459-y#Sec10" target="_blank">imaging</a>.<br><br>Co-author Larry Lyons of UCLA explained the process of putting the data together to form the models to <a href="https://www.nbcnews.com/science/space/space-hurricane-rained-electrons-observed-first-time-rcna328" target="_blank">NBC</a>:<br><br>"We had various instruments measuring various things at different times, so it wasn't like we took a big picture and could see it. The really fun thing about this type of work is that we had to piece together bits of information and put together the whole picture."<br><br>He further mentioned that these findings were completely unexpected and that nobody that even theorized a thing like this could exist. <br></p><p>While this storm wasn't a threat to any life on Earth, a storm like this could have noticeable effects on space weather. This study suggests that this could have several effects, including "increased satellite drag, disturbances in High Frequency (HF) radio communications, and increased errors in over-the-horizon radar location, satellite navigation, and communication systems."</p><p>The authors <a href="https://www.nature.com/articles/s41467-021-21459-y#Sec8" target="_blank" rel="noopener noreferrer">speculate</a> that these "space hurricanes" could also exist in the magnetospheres of other planets.</p><p>Lead author Professor Qing-He Zhang of Shandong University discussed how these findings will influence our understanding of the magnetosphere and its changes with <a href="https://www.eurekalert.org/pub_releases/2021-03/uor-sho030221.php" target="_blank" rel="noopener noreferrer">EurekaAlert</a>:</p><p>"This study suggests that there are still existing local intense geomagnetic disturbance and energy depositions which is comparable to that during super storms. This will update our understanding of the solar wind-magnetosphere-ionosphere coupling process under extremely quiet geomagnetic conditions."</p>
The chariot survived ancient eruptions and modern-day looters to become a part of the world heritage site.
- Archeologists recently discovered a first-of-its-kind chariot in Pompeii.
- The ceremonial chariot is decorated with bronze and tin medallions, while the sides sport bronzesheets and red-and-black paintings.
- Given looting activity in the area, it's lucky the 2,000-year-old treasure wasn't lost to the world heritage site.
One dope Pompeian whip<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNTcxOTUzNS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY2MjU3Nzk5MH0.M3HW5tPe17JuKMhLtKgbOlqK4sMbspqYskR_jz6t9sg/img.jpg?width=1245&coordinates=0%2C70%2C0%2C230&height=700" id="497f9" class="rm-shortcode" data-rm-shortcode-id="1bda1a9c489b85c8a56c189eb21706d1" data-rm-shortcode-name="rebelmouse-image" data-width="1245" data-height="700" />
Researchers carefully extract the chariot from the sedimentary rock encasing it.
(Photo: Archaeological Park of Pompeii)<p>In a recent discovery, researchers unearthed a first-of-its-kind chariot at Civita Giuliana, an excavation site north of Pompeii's ancient walls. In Roman times, the site served as a getaway for Rome's elite and wealthy citizens, a serene countryside brimming with villas and Mediterranean farms. So, it's understandable why such an exquisite chariot was found here.</p><p>"I was astounded," Eric Poehler, a professor at the University of Massachusetts Amherst, who specializes in Pompeii traffic, <a href="https://www.npr.org/2021/02/27/972118983/a-lamborghini-of-chariots-is-discovered-at-pompeii-archaeologists-are-wowed?ft=nprml&f=1001" target="_blank">told <em>NPR</em></a>. "Many of the vehicles I'd written about before ... are your standard station wagon or vehicle for taking the kids to soccer. This is a Lamborghini. This is an outright fancy, fancy car."</p><p>Located in a double-level portico, the chariot is a far cry from anything Ben-Hur would have been seen cruising around in. It sports four iron wheels and a high seat complete with arm- and backrest. The sides are adorned with engraved bronze and wooden panels painted with red-and-black figures. And the rear bumps with a register of bronze and tin medallion depicting Eros-inspired scenes of satyrs, nymphs, and cupids. In short, this chariot is slab.</p><p>"It is an extraordinary discovery for the advancement of our knowledge of the ancient world," Massimo Osanna, the director of the archaeological park, <a href="http://pompeiisites.org/en/comunicati/the-four-wheeled-processional-chariot-the-last-discovery-of-pompeii/" target="_blank" rel="noopener noreferrer">said in a statement</a>. "At Pompeii vehicles used for transport have been found in the past, […] but nothing like the Civita Giuliana chariot."</p><p>But unlike a Lamborghini—which serves only to show the owner has more money than sense—this chariot served a social and cultural role. Likely a <em>pilentum</em>, it would have been rolled out in times of ceremony, potentially during festivals, processions, or weddings.</p><p>While similar chariots have been uncovered in northern Greece, this is the first such chariot to be discovered in Italy. Its presence in Pompeii will further help historians understand the people who called the city home, as well as their relation to the Mediterranean world.</p><p>As Poehler added, "This is precisely the kind of find that one wants to find at Pompeii, the really well-articulated, very well-preserved moments in time. And it happens to be in this case an object that is relatively rare despite its ubiquity in the past."</p>
It belongs in a museum (not the black market)<p>Beyond its gilded appeal, the chariot is also special because it survived so we could learn from it. The area where the vehicle was found has been favored in recent years by looters, and illicit tunnels had been dug precariously close to the chariot's resting place. For this reason, the archeological park has teamed up with the Public Prosecutor's Office of Torre Annunziata to protect Pompeii's history and excavate its treasures before they become lost or stolen.</p><p>"The collaboration between the Public Prosecutor's Office of Torre Annunziata and the Archaeological Park of Pompeii has proved itself to be a formidable instrument, not only for bringing finds of exceptional historical and artistic value to light, but also for halting the criminal actions of individuals who for years have been the protagonists in a systematic looting of the priceless archaeological heritage preserved in the vast area of the Civita Giuliana villa, which is still largely buried and to which the recent exceptional findings bear witness," Nunzio Fragliasso, chief prosecutor of Torre Annunziata, said in his joint statement with Osanna.</p><p>Nor is everything that glitters historic gold. Even Pompeii's everyday ephemera can have an outsized impact on history. Pompeian citizens, for example, viewed street walls as a type of "<a href="https://www.thegreatcoursesdaily.com/how-pompeii-graffiti-preserved-the-ordinary-voices-of-ancient-rome/" target="_blank">public advertisement space</a>" and so painted them thick with graffiti. As historians must often rely on the written works of the literate elite, this graffiti gives the ordinary Pompeians their voice back. <a href="https://www.sciencemag.org/news/2018/10/ancient-graffiti-shifts-date-pompeii-s-destruction-back-2-months" target="_blank" rel="noopener noreferrer">One such charcoal tag</a> even corrected the record of Vesuvius's eruption by two months, from August to October, contradicting the traditionally accepted date set by Pliny the Younger.</p><p>"Today, archaeologists try to understand ancient societies by studying the entire material record -- not just the beautiful or luxurious objects, but also the broken bits of cooking pottery, the animal bones thrown into the trash, the microscopic grains of pollen in the soil, and much more," Caitlín Barrett, associate professor at Cornell University, <a href="https://www.cnn.com/travel/article/pompeii-new-excavations-looting/index.html" target="_blank" rel="noopener noreferrer">told <em>CNN</em></a>.</p><p>This ephemera is also at risk. Looters looking for eye-catching treasure and artwork will often destroy everyday objects in their pursuit. And after centuries encased in protective sedimentary rock, the city has again been exposed to the rains, winds, and human blunders that erode. The goal now isn't just to excavate fantastic treasures, but to preserve the world heritage site and learn from it for as long as time (<a href="http://volcano.oregonstate.edu/what%E2%80%99s-most-recent-eruption-vesuvius-and-will-it-erupt-again" target="_blank" rel="noopener noreferrer">and maybe Vesuvius</a>) will allow.</p>
New study suggests the placebo effect can be as powerful as microdosing LSD.
- New research from Imperial College London investigated the psychological effects of microdosing LSD in 191 volunteers.
- While microdosers experienced beneficial mental health effects, the placebo group performed statistically similar to those who took LSD.
- Researchers believe the expectation of a trip could produce some of the same sensations as actually ingesting psychedelics.
Psychedelics: The scientific renaissance of mind-altering drugs | Sam Harris, Michael Pollan & more<span style="display:block;position:relative;padding-top:56.25%;" class="rm-shortcode" data-rm-shortcode-id="92360c805fe66c11de38a75b0967f417"><iframe type="lazy-iframe" data-runner-src="https://www.youtube.com/embed/5T0LmbWROKY?rel=0" width="100%" height="auto" frameborder="0" scrolling="no" style="position:absolute;top:0;left:0;width:100%;height:100%;"></iframe></span><p>Published in <em>eLife</em>, the team recruited 191 citizen cosmonauts to microdose either LSD or a placebo over the course of several weeks and note the psychological effects. Volunteers were already microdosing LSD, so there was no true control. Each volunteer was given instructions on creating their own low-dose gel capsules, some containing LSD, others not. Then they mixed the capsules in envelopes so they didn't know if they were taking the real thing or not.</p><p>The trial design was ingenious: each capsule featured a QR code that was scanned after the addition of ingredients but before they were placed in the envelope so that researchers knew what they were ingesting.</p><p>The problem: volunteers sourced their own LSD. Lack of quality control could have had a profound effect on the results. </p><p>The results: LSD microdosers reported feeling more mindful, satisfied with life, and better overall; they also noticed a reduction in feelings of paranoia. </p><p>The catch: the control group felt the same thing, with no statistical difference between the groups. </p><p>Lead author Balázs Szigeti comments on the findings: "This suggests that the improvements may not be due to the pharmacological action of the drug but can instead be explained by the placebo effect." </p>
Photo: Alexander / Adobe Stock<p>Psychedelics are notoriously difficult to control for given the intensity of the experience. Yet there is precedent for the above findings. A <a href="https://link.springer.com/article/10.1007/s00213-020-05464-5" target="_blank">2019 study</a> found that 61 percent of volunteers that took a placebo instead of psilocybin felt some psychedelic effects, with a few volunteers experiencing full-on trips.</p><p style="margin-left: 20px;">"Several stated that they saw the paintings on the walls 'move' or 'reshape' themselves, others felt 'heavy. . . as if gravity [had] a stronger hold', and one had a 'come down' before another 'wave' hit her."</p><p>The Imperial team believes the expectation of a trip might have been enough to produce similar results. Senior author David Erritzoe is excited for future studies on the topic, believing they tapped into a new wave of citizen science that could push forward our knowledge of psychedelic substances.</p><p style="margin-left: 20px;">"Accounting for the placebo effect is important when assessing trends such as the use of cannabidiol oils, fad diets or supplements where social pressure or users' expectations can lead to a strong placebo response. Self-blinding citizen science initiatives could be used as an inexpensive, initial screening tool before launching expensive clinical studies."</p><p>As investments into the psychedelics market explode, with one company <a href="https://www.bloomberg.com/news/articles/2021-03-03/thiel-backed-magic-mushroom-firm-atai-hits-2-billion-valuation" target="_blank">reaching a $2 billion valuation</a>, a recurring irony appears in the long arc of psychedelics and research: the power of our minds might be enough to feel greater life satisfaction and a deeper sense of mindfulness. If that's possible with a placebo, we have to question why the rush to create more pharmacology is necessary. </p><p>This is, mind you, a separate conversation over the role of psychedelics and rituals for group bonding. The function of group cohesion around consciousness-altering substances will continue to play an important role in many communities. </p><p>Of course, we should continue to explore the efficacy of psychedelics on anxiety, depression, suicidal ideation, PTSD, and addiction. <a href="https://bigthink.com/surprising-science/antidepressant-effects" target="_self">Pharmacological dependence</a> is a stain on the psychiatry industry. Whether or not psychedelics can be prescribed for daily use remains to be seen, but we know a moneyed interest is expecting a return on investment—the above company, ATAI Life Sciences, raised $157 million in its Series D round. </p><p>When it comes to wellbeing, some things money just can't buy. How we navigate the tricky terrain of mainstreaming psychedelics remains to be seen. </p><p>--</p><p><em>Stay in touch with Derek on <a href="http://www.twitter.com/derekberes" target="_blank">Twitter</a> and <a href="https://www.facebook.com/DerekBeresdotcom" target="_blank" rel="noopener noreferrer">Facebook</a>. His most recent book is</em> "<em><a href="https://www.amazon.com/gp/product/B08KRVMP2M?pf_rd_r=MDJW43337675SZ0X00FH&pf_rd_p=edaba0ee-c2fe-4124-9f5d-b31d6b1bfbee" target="_blank" rel="noopener noreferrer">Hero's Dose: The Case For Psychedelics in Ritual and Therapy</a>."</em></p>
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