Is Alzheimer's Research On the Wrong Track?
"The graveyard of hope." That's what experts call the quest for effective Alzheimer's treatments, a two-decade effort that has been marked by one costly and high-profile failure after another. Nearly all of the drugs tested target one of the key hallmarks of Alzheimer's disease: amyloid plaques, the barnacle-like proteins long considered the culprits behind the memory-robbing ravages of the disease. Yet all the anti-amyloid drugs have flopped miserably, prompting some scientists to believe we've fingered the wrong villain.
"We're flogging a dead horse," says Peter Davies, PhD, an Alzheimer's researcher at the Feinstein Institute for Medical Research in New York. "The fact that no one's gotten better suggests that you have the wrong mechanism."
If the naysayers are right, how could a scientific juggernaut of this magnitude—involving hundreds of scientists in academia and industry at a cost of tens of billions of dollars--be so far off the mark? There are no easy answers, but some experts believe this calls into question how research is conducted and blame part of the failure on the insular culture of the scientific aristocracy at leading academic institutions.
"The field began to be dominated by narrow views."
"The field began to be dominated by narrow views," says George Perry, PhD, an Alzheimer's researcher and dean of the College of Sciences at the University of Texas in San Antonio. "The people pushing this were incredibly articulate, powerful and smart. They'd go to scientific meetings and all hang around with each other and they'd self-reinforce."
In fairness, there was solid science driving this. Post-mortem analyses of Alzheimer's patients found their brains were riddled with amyloid plaques. People with a strong family history of Alzheimer's had genetic mutations in the genes that encode for the production of amyloids. And in animal studies, scientists found that if amyloids were inserted into the brains of transgenic mice, they exhibited signs of memory loss. Remove the amyloids and they suddenly got better. This body of research helped launch the Amyloid Cascade Hypothesis of the disease in 1992—which has driven research ever since.
Scientists believed that the increase in the production of these renegade proteins, which form sticky plaques and collect outside of the nerve cells in the brain, triggers a series of events that interfere with the signaling system between synapses. This seems to prevent cells from relaying messages or talking to each other, causing memory loss, confusion and increasing difficulties doing the normal tasks of life. The path forward seemed clear: stop amyloid production and prevent disease progression. "We were going after the obvious abnormality," says Dr. David Knopman, a neurologist and Alzheimer's researcher at the Mayo Clinic in Rochester, Minnesota.
"Why wouldn't you do that?" Why ideed.
In hindsight, though, there was no real smoking gun—no one ever showed precisely how the production of amyloids instigates the destruction of vital brain circuits.
"Amyloids are clearly important," says Perry, "but they have not proven to be necessary and sufficient for the development of this disease."
Ironically, there have been hints all along that amyloids may not be toxic bad boys.
A handful of studies revealed that amyloid proteins are produced in healthy brains to protect synapses. Research on animal models that mimic diseases suggest that certain forms of amyloids can ease damage from strokes, traumatic brain injuries and even heart attacks. In a 2013 study, to cite just one example, a Stanford University team injected synthetic amyloids into paralyzed mice with an inflammatory disorder similar to multiple sclerosis. Instead of worsening their symptoms—which is what the researchers expected to happen--the mice could suddenly walk again. Remove the amyloids, and they became paralyzed once more.
Still other studies suggest amyloids may actually function as molecular guardians dispatched to silence inflammation and mop up errant cells after an injury as part of the body's waste management system. "The presence of amyloids is a protective response to something going wrong, a threat," says Dr. Dale Bredesen, a UCLA neurologist. "But the problem arises when the threats are chronic, multiple, unrelenting and intense. The defenses the brain mounts are also intense and these protective mechanisms cross the line into causing harm, and killing the very synapses and brain cells the amyloid was called up to protect."
So how did research get derailed?
In a way, we're victims of our own success, critics say.
Early medical triumphs in the heady post-World War II era, like the polio vaccine that eradicated the crippling childhood killer, or antibiotics, reinforced the magic bullet idea of curing disease--find a target and then hit it relentlessly. That's why when scientists made the link between amyloids and disease progression, Big Pharma jumped on the bandwagon in hopes of inventing a trillion-dollar drug. This approach is fine when you have an acute illness, like an infectious disease that's caused by one agent, but not for something as complicated as Alzheimer's.
The other piece of the problem is the dwindling federal dollars for basic research. Maverick scientists find it difficult to secure funding, which means that other possible targets or approaches remained relatively unexplored—and drug companies are understandably reluctant to sponsor fishing expeditions with little guarantee of a payoff. "Very influential people were driving this hypothesis," says Davies, and with careers on the line, "there was not enough objectivity or skepticism about that hypothesis."
Still, no one is disputing the importance of anti-amyloid drugs—and ongoing clinical trials, like the DIAN and A4 studies, are intervening earlier in patients who are at a high risk of developing Alzheimer's, but before they're symptomatic. "The only way to know if this is really a dead end is if you take it as far as it can go," says Knopman. "I believe the A4 study is the proper way to test the amyloid hypothesis."
But according to some experts, the latest thinking is that Alzheimer's is triggered by a range of factors, including genetics, poor diet, stress and lack of exercise.
"Alzheimer's is like other chronic age-related diseases and is multi-factorial," says Perry. "Modulating amyloids may have value but other avenues need to be explored."
After spaceflight record, NASA looks to protect astronauts on even longer trips
At T-minus six seconds, the main engines of the Atlantis Space Shuttle ignited, rattling its capsule “like a skyscraper in an earthquake,” according to astronaut Tom Jones, describing the 1988 launch. As the rocket lifted off and accelerated to three times the force of Earth's gravity, “It felt as if two of my friends were standing on my chest and wouldn’t get off.” But when Atlantis reached orbit, the main engines cut off, and the astronauts were suddenly weightless.
Since 1961, NASA has sent hundreds of astronauts into space while working to making their voyages safer and smoother. Yet, challenges remain. Weightlessness may look amusing when watched from Earth, but it has myriad effects on cognition, movement and other functions. When missions to space stretch to six months or longer, microgravity can impact astronauts’ health and performance, making it more difficult to operate their spacecraft.
Yesterday, NASA astronaut Frank Rubio returned to Earth after over one year, the longest single spaceflight for a U.S. astronaut. But this is just the start; longer and more complex missions into deep space loom ahead, from returning to the moon in 2025 to eventually sending humans to Mars. To ensure that these missions succeed, NASA is increasing efforts to study the biological effects and prevent harm.
The dangers of microgravity are real
A NASA report published in 2016 details a long list of incidents and near-misses caused – at least partly – by space-induced changes in astronauts’ vision and coordination. These issues make it harder to move with precision and to judge distance and velocity.
According to the report, in 1997, a resupply ship collided with the Mir space station, possibly because a crew member bumped into the commander during the final docking maneuver. This mishap caused significant damage to the space station.
Returns to Earth suffered from problems, too. The same report notes that touchdown speeds during the first 100 space shuttle landings were “outside acceptable limits. The fastest landing on record – 224 knots (258 miles) per hour – was linked to the commander’s momentary spatial disorientation.” Earlier, each of the six Apollo crews that landed on the moon had difficulty recognizing moon landmarks and estimating distances. For example, Apollo 15 landed in an unplanned area, ultimately straddling the rim of a five-foot deep crater on the moon, harming one of its engines.
Spaceflight causes unique stresses on astronauts’ brains and central nervous systems. NASA is working to reduce these harmful effects.
NASA
Space messes up your brain
In space, astronauts face the challenges of microgravity, ionizing radiation, social isolation, high workloads, altered circadian rhythms, monotony, confined living quarters and a high-risk environment. Among these issues, microgravity is one of the most consequential in terms of physiological changes. It changes the brain’s structure and its functioning, which can hurt astronauts’ performance.
The brain shifts upwards within the skull, displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes.
That’s partly because of how being in space alters blood flow. On Earth, gravity pulls our blood and other internal fluids toward our feet, but our circulatory valves ensure that the fluids are evenly distributed throughout the body. In space, there’s not enough gravity to pull the fluids down, and they shift up, says Rachael D. Seidler, a physiologist specializing in spaceflight at the University of Florida and principal investigator on many space-related studies. The head swells and legs appear thinner, causing what astronauts call “puffy face chicken legs.”
“The brain changes at the structural and functional level,” says Steven Jillings, equilibrium and aerospace researcher at the University of Antwerp in Belgium. “The brain shifts upwards within the skull,” displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes. Some of the displaced cerebrospinal fluid goes into cavities within the brain, called ventricles, enlarging them. “The remaining fluids pool near the chest and heart,” explains Jillings. After 12 consecutive months in space, one astronaut had a ventricle that was 25 percent larger than before the mission.
Some changes reverse themselves while others persist for a while. An example of a longer-lasting problem is spaceflight-induced neuro-ocular syndrome, which results in near-sightedness and pressure inside the skull. A study of approximately 300 astronauts shows near-sightedness affects about 60 percent of astronauts after long missions on the International Space Station (ISS) and more than 25 percent after spaceflights of only a few weeks.
Another long-term change could be the decreased ability of cerebrospinal fluid to clear waste products from the brain, Seidler says. That’s because compressing the brain also compresses its waste-removing glymphatic pathways, resulting in inflammation, vulnerability to injuries and worsening its overall health.
The effects of long space missions were best demonstrated on astronaut twins Scott and Mark Kelly. This NASA Twins Study showed multiple, perhaps permanent, changes in Scott after his 340-day mission aboard the ISS, compared to Mark, who remained on Earth. The differences included declines in Scott’s speed, accuracy and cognitive abilities that persisted longer than six months after returning to Earth in March 2016.
By the end of 2020, Scott’s cognitive abilities improved, but structural and physiological changes to his eyes still remained, he said in a BBC interview.
“It seems clear that the upward shift of the brain and compression of the surrounding tissues with ventricular expansion might not be a good thing,” Seidler says. “But, at this point, the long-term consequences to brain health and human performance are not really known.”
NASA astronaut Kate Rubins conducts a session for the Neuromapping investigation.
NASA
Staying sharp in space
To investigate how prolonged space travel affects the brain, NASA launched a new initiative called the Complement of Integrated Protocols for Human Exploration Research (CIPHER). “CIPHER investigates how long-duration spaceflight affects both brain structure and function,” says neurobehavioral scientist Mathias Basner at the University of Pennsylvania, a principal investigator for several NASA studies. “Through it, we can find out how the brain adapts to the spaceflight environment and how certain brain regions (behave) differently after – relative to before – the mission.”
To do this, he says, “Astronauts will perform NASA’s cognition test battery before, during and after six- to 12-month missions, and will also perform the same test battery in an MRI scanner before and after the mission. We have to make sure we better understand the functional consequences of spaceflight on the human brain before we can send humans safely to the moon and, especially, to Mars.”
As we go deeper into space, astronauts cognitive and physical functions will be even more important. “A trip to Mars will take about one year…and will introduce long communication delays,” Seidler says. “If you are on that mission and have a problem, it may take eight to 10 minutes for your message to reach mission control, and another eight to 10 minutes for the response to get back to you.” In an emergency situation, that may be too late for the response to matter.
“On a mission to Mars, astronauts will be exposed to stressors for unprecedented amounts of time,” Basner says. To counter them, NASA is considering the continuous use of artificial gravity during the journey, and Seidler is studying whether artificial gravity can reduce the harmful effects of microgravity. Some scientists are looking at precision brain stimulation as a way to improve memory and reduce anxiety due to prolonged exposure to radiation in space.
Other scientists are exploring how to protect neural stem cells (which create brain cells) from radiation damage, developing drugs to repair damaged brain cells and protect cells from radiation.
To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
Additionally, NASA is scrutinizing each aspect of the mission, including astronaut exercise, nutrition and intellectual engagement. “We need to give astronauts meaningful work. We need to stimulate their sensory, cognitive and other systems appropriately,” Basner says, especially given their extreme confinement and isolation. The scientific experiments performed on the ISS – like studying how microgravity affects the ability of tissue to regenerate is a good example.
“We need to keep them engaged socially, too,” he continues. The ISS crew, for example, regularly broadcasts from space and answers prerecorded questions from students on Earth, and can engage with social media in real time. And, despite tight quarters, NASA is ensuring the crew capsule and living quarters on the moon or Mars include private space, which is critical for good mental health.
Exploring deep space builds on a foundation that began when astronauts first left the planet. With each mission, scientists learn more about spaceflight effects on astronauts’ bodies. NASA will be using these lessons to succeed with its plans to build science stations on the moon and, eventually, Mars.
“Through internally and externally led research, investigations implemented in space and in spaceflight simulations on Earth, we are striving to reduce the likelihood and potential impacts of neurostructural changes in future, extended spaceflight,” summarizes NASA scientist Alexandra Whitmire. To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
A newly discovered brain cell may lead to better treatments for cognitive disorders
Swiss researchers have discovered a third type of brain cell that appears to be a hybrid of the two other primary types — and it could lead to new treatments for many brain disorders.
The challenge: Most of the cells in the brain are either neurons or glial cells. While neurons use electrical and chemical signals to send messages to one another across small gaps called synapses, glial cells exist to support and protect neurons.
Astrocytes are a type of glial cell found near synapses. This close proximity to the place where brain signals are sent and received has led researchers to suspect that astrocytes might play an active role in the transmission of information inside the brain — a.k.a. “neurotransmission” — but no one has been able to prove the theory.
A new brain cell: Researchers at the Wyss Center for Bio and Neuroengineering and the University of Lausanne believe they’ve definitively proven that some astrocytes do actively participate in neurotransmission, making them a sort of hybrid of neurons and glial cells.
According to the researchers, this third type of brain cell, which they call a “glutamatergic astrocyte,” could offer a way to treat Alzheimer’s, Parkinson’s, and other disorders of the nervous system.
“Its discovery opens up immense research prospects,” said study co-director Andrea Volterra.
The study: Neurotransmission starts with a neuron releasing a chemical called a neurotransmitter, so the first thing the researchers did in their study was look at whether astrocytes can release the main neurotransmitter used by neurons: glutamate.
By analyzing astrocytes taken from the brains of mice, they discovered that certain astrocytes in the brain’s hippocampus did include the “molecular machinery” needed to excrete glutamate. They found evidence of the same machinery when they looked at datasets of human glial cells.
Finally, to demonstrate that these hybrid cells are actually playing a role in brain signaling, the researchers suppressed their ability to secrete glutamate in the brains of mice. This caused the rodents to experience memory problems.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Andrea Volterra, University of Lausanne.
But why? The researchers aren’t sure why the brain needs glutamatergic astrocytes when it already has neurons, but Volterra suspects the hybrid brain cells may help with the distribution of signals — a single astrocyte can be in contact with thousands of synapses.
“Often, we have neuronal information that needs to spread to larger ensembles, and neurons are not very good for the coordination of this,” researcher Ludovic Telley told New Scientist.
Looking ahead: More research is needed to see how the new brain cell functions in people, but the discovery that it plays a role in memory in mice suggests it might be a worthwhile target for Alzheimer’s disease treatments.
The researchers also found evidence during their study that the cell might play a role in brain circuits linked to seizures and voluntary movements, meaning it’s also a new lead in the hunt for better epilepsy and Parkinson’s treatments.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Volterra.