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."
A new paper reveals that the Voyager 1 spacecraft detected a constant hum coming from outside our Solar System.
Voyager 1, humanity's most faraway spacecraft, has detected an unusual "hum" coming from outside our solar system. Fourteen billion miles away from Earth, the Voyager's instruments picked up a droning sound that may be caused by plasma (ionized gas) in the vast emptiness of interstellar space.
Launched in 1977, the Voyager 1 space probe — along with its twin Voyager 2 — has been traveling farther and farther into space for over 44 years. It has now breached the edge of our solar system, exiting the heliosphere, the bubble-like region of space influenced by the sun. Now, the spacecraft is moving through the "interstellar medium," where it recorded the peculiar sound.
Stella Koch Ocker, a doctoral student in astronomy at Cornell University, discovered the sound in the data from the Voyager's Plasma Wave System (PWS), which measures electron density. Ocker called the drone coming from plasma shock waves "very faint and monotone," likely due to the narrow bandwidth of its frequency.
While they think the persistent background hum may be coming from interstellar gas, the researchers don't yet know what exactly is causing it. It might be produced by "thermally excited plasma oscillations and quasi-thermal noise."
The new paper from Ocker and her colleagues at Cornell University and the University of Iowa, published in Nature Astronomy, also proposes that this is not the last we'll hear of the strange noise. The scientists write that "the emission's persistence suggests that Voyager 1 may be able to continue tracking the interstellar plasma density in the absence of shock-generated plasma oscillation events."
Voyager Captures Sounds of Interstellar Space www.youtube.com
The researchers think the droning sound may hold clues to how interstellar space and the heliopause, which can be thought of as the solar's system border, may be affecting each other. When it first entered interstellar space, the PWS instrument reported disturbances in the gas caused by the sun. But in between such eruptions is where the researchers spotted the steady signature made by the near-vacuum.
Senior author James Cordes, a professor of astronomy at Cornell, compared the interstellar medium to "a quiet or gentle rain," adding that "in the case of a solar outburst, it's like detecting a lightning burst in a thunderstorm and then it's back to a gentle rain."
More data from Voyager over the next few years may hold crucial information to the origins of the hum. The findings are already remarkable considering the space probe is functioning on technology from the mid-1970s. The craft has about 70 kilobytes of computer memory. It also carries a Golden Record created by a committee chaired by the late Carl Sagan, who taught at Cornell University. The 12-inch gold-plated copper disk record is essentially a time capsule, meant to tell the story of Earthlings to extraterrestrials. It contains sounds and images that showcase the diversity of Earth's life and culture.
- Lawrence Kohlberg's experiments gave children a series of moral dilemmas to test how they differed in their responses across various ages.
- He identified three separate stages of moral development from the egoist to the principled person.
- Some people do not progress through all the stages of moral development, which means they will remain "morally undeveloped."
Has your sense of right and wrong changed over the years? Are there things that you see as acceptable today that you'd never dream of doing when you were younger? If you spend time around children, do you notice how starkly different their sense of morality is? How black and white, or egocentric, or oddly rational it can be?
These were questions that Lawrence Kohlberg asked, and his "stages of moral development" dominates a lot of moral psychology today.
The Heinz Dilemma
Kohlberg was curious to see how and why children differed in their ethical judgements, and so he gave roughly 60 children, across a variety of ages, a series of moral dilemmas. They were all given open-ended questions to explain their answers in order to minimize the risk of leading them to a certain response.
For instance, one of the better-known dilemmas involved an old man called Heinz who needed an expensive drug for his dying wife. Heinz only managed to raise half the required money, which the pharmacists wouldn't accept. Unable to afford it, he has only three options. What should he do?
(a) Not steal it because it's breaking the law.
(b) Steal it, and go to jail for breaking the law.
(c) Steal it, but be let off a prison sentence.
What option would you choose?
Stages of Moral Development
From the answers he got, Kohlberg identified three definite levels or stages of our moral development.
Pre-conventional stage. This is characterized by an ego-centric attitude that seeks pleasure and to prevent pain. The primary motivation is to avoid punishment or claim a reward. In this stage of moral development, "good" is defined as whatever is beneficial to oneself. "Bad" is the opposite. For instance, a young child might share their food with a younger sibling not from kindness or some altruistic impulse but because they know that they'll be praised by their parents (or, perhaps, have their food taken away from them).
In the pre-conventional stage, there is no inherent sense of right and wrong, per se, but rather "good" is associated with reward and "bad" is associated with punishment. At this stage, children are sort of like puppies.
If you spend time around children, do you notice how starkly different their sense of morality is? How black and white, or egocentric, or oddly rational it can be?
Conventional stage. This stage reflects a growing sense of social belonging and hence a higher regard for others. Approval and praise are seen as rewards, and behavior is calibrated to please others, obey the law, and promote the good of the family/tribe/nation. In the conventional stage, a person comes to see themselves as part of a community and that their actions have consequences.
Consequently, this stage is much more rule-focused and comes along with a desire to be seen as good. Image, reputation, and prestige matter the most in motivating good behavior — we want to fit into our community.
Post-conventional stage. In this final stage, there is much more self-reflection and moral reasoning, which gives people the capacity to challenge authority. Committing to principles is considered more important than blindly obeying fixed laws. Importantly, a person comes to understand the difference between what is "legal" and what is "right." Ideas such as justice and fairness start to mature. Laws or rules are no longer equated to morality but might be seen as imperfect manifestations of larger principles.
A lot of moral philosophy is only possible in the post-conventional stage. Theories like utilitarianism or Immanuel Kant's duty-focused ethics ask us to consider what's right or wrong in itself, not just because we get a reward or look good to others. Aristotle perhaps sums it up best when he wrote, "I have gained this from philosophy: that I do without being commanded what others do only from fear of the law."
How morally developed are you?
Kohlberg identified these stages as a developmental progression from early infancy all the way to adulthood, and they map almost perfectly onto Jean Piaget's psychology of child development. For instance, the pre-conventional stage usually lasts from birth to roughly nine years old, the conventional occurs mainly during adolescence, and the post-conventional goes into adulthood.
What's important to note, though, is that this is not a fatalistic timetable to which all humans adhere. Kohlberg thought, for instance, that some people never progress or mature. It's quite possible, maybe, for someone to have no actual moral compass at all (which is sometimes associated with psychopathy).
More commonly, though, we all know people who are resolutely bound to the conventional stage, where they care only for their image or others' judgment. Those who do not develop beyond this stage are usually stubbornly, even aggressively, strict in following the rules or the law. Prepubescent children can be positively authoritarian when it comes to obeying the rules of a board game, for instance.
So, what's your answer to the Heinz dilemma? Where do you fall on Kohlberg's moral development scale? Is he right to view it is a progressive, hierarchical maturing, where we have "better" and "worse" stages? Or could it be that as we grow older, we grow more immoral?
Dunbar's number is a popular estimate for the maximum size of social groups. But new research suggests that it's a fictitious number based on flimsy data and bad theory.
- A team of researchers recalculated Dunbar's number using his original methods and better data.
- Their estimates were as high as 520 and were stretched over a wide enough range as to be nearly useless.
- The authors suggest that the method used to calculate the number of friends a person can have is also theoretically unsound.
Since 1992, people have been talking about "Dunbar's number," the supposed upper limit of the number of people with whom a person can maintain stable social relationships. Named for British anthropologist Robin Dunbar, its value, rounded from 148 to 150, has permeated both professional and popular culture.
The Swedish taxation authority keeps offices under 150 people as a result of it, and the standard facilities of the W. L. Gore and Associates company are based around the concept. Dunbar's number was cited in Malcolm Gladwell's bestselling book Tipping Point, and it also has a fair amount of academic influence, the original paper having been cited 2,500 times.
It's also probably wrong.
Despite its fame, Dunbar's number has always been controversial. A new study out of Sweden and published in the journal Biology Letters suggests it might be both theoretically and empirically unsound.
Getting to 150
Less well known than the value of Dunbar's number is how he came up with it. The value of 150 is determined by looking at the ratio between the size of the neocortex in primates and the average size of groups they form. These ratios were then applied to data on the human brain, and the average value of roughly 150 relationships was determined.
The point of this study isn't to replace Dunbar's number but to dismiss the notion that such a number can be determined in the first place.
However, this number has always been the subject of debate. An alternative value based on empirical studies of American social groups is a much higher 291, nearly double that of Dunbar, and suggests that the median social network has 231 people in it. That value wasn't calculated by crunching other numbers; it kept coming up again and again when the authors of that study looked at the professional and social networks cultivated by different groups of people.
Yet, even in the face of critics and new studies, Dunbar's number always managed to hang on in popular and academic discourse. That is where this latest study comes in.
A new study with old methods but better data
In the new study, the researchers did similar calculations as Dunbar but with updated information on the size of monkey brains and social networks. While their average human group size was below Dunbar's estimate, the upper boundary of the 95 percent confidence interval ranged between 2 and 520 people depending on what methods were used. Nearly every method gave a range of possibilities with a maximum value higher than 150.
When the authors applied Dunbar's exact same methods from 1992 to their new data, they got an average group size of 69 people — but a 95% confidence interval between roughly 5 and 292. This is far too wide a range to be of any use.
Additionally, the authors discuss the flimsy nature of the theory behind Dunbar's number. Human brains often work differently than those of our nearest evolutionary cousins, as evidenced by our ability to create things like, "Stockholm, symphonies, and science." The idea that we would process social information exactly like other apes do is a bold and largely unsubstantiated claim.
They quote a study by Jan De Ruiter and their rejection of the idea that the ratio between monkey neocortex size and group composition can be carried over to humans:
"Dunbar's assumption that the evolution of human brain physiology corresponds with a limit in our capacity to maintain relationships ignores the cultural mechanisms, practices, and social structures that humans develop to counter potential deficiencies"
So, is there a new Dunbar number?
The point of this study isn't to replace Dunbar's number but to dismiss the notion that such a number can be determined in the first place. The authors go so far as to end their paper with:
"It is our hope, though perhaps futile, that this study will put an end to the use of 'Dunbar's number' within science and in popular media. 'Dunbar's number' is a concept with limited theoretical foundation lacking empirical support."
While this study may not be the death of Dunbar's number — after all, less empirically sound ideas have endured much longer — it may be the foundation for new attempts to determine how large our meaningful and stable social groups can be.
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