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."
A startup aims to make medicines in space
Story by Big Think
On June 12, a SpaceX Falcon 9 rocket deployed 72 small satellites for customers — including the world’s first space factory.
The challenge: In 2019, pharma giant Merck revealed that an experiment on the International Space Station had shown how to make its blockbuster cancer drug Keytruda more stable. That meant it could now be administered via a shot rather than through an IV infusion.
The key to the discovery was the fact that particles behave differently when freed from the force of gravity — seeing how its drug crystalized in microgravity helped Merck figure out how to tweak its manufacturing process on Earth to produce the more stable version.
Microgravity research could potentially lead to many more discoveries like this one, or even the development of brand-new drugs, but ISS astronauts only have so much time for commercial experiments.
“There are many high-performance products that are only possible to make in zero-gravity, which is a manufacturing capability that cannot be replicated in any factory on Earth.”-- Will Bruey.
The only options for accessing microgravity (or free fall) outside of orbit, meanwhile, are parabolic airplane flights and drop towers, and those are only useful for experiments that require less than a minute in microgravity — Merck’s ISS experiment took 18 days.
The idea: In 2021, California startup Varda Space Industries announced its intention to build the world’s first space factory, to manufacture not only pharmaceuticals but other products that could benefit from being made in microgravity, such as semiconductors and fiber optic cables.
This factory would consist of a commercial satellite platform attached to two Varda-made modules. One module would contain equipment capable of autonomously manufacturing a product. The other would be a reentry capsule to bring the finished goods back to Earth.
“There are many high-performance products that are only possible to make in zero-gravity, which is a manufacturing capability that cannot be replicated in any factory on Earth,” said CEO Will Bruey, who’d previously developed and flown spacecraft for SpaceX.
“We have a team stacked with aerospace talent in the prime of their careers, focused on getting working hardware to orbit as quickly as possible,” he continued.
“[Pharmaceuticals] are the most valuable chemicals per unit mass. And they also have a large market on Earth.” -- Will Bruey, CEO of Varda Space.
What’s new? At the time, Varda said it planned to launch its first space factory in 2023, and, in what feels like a first for a space startup, it has actually hit that ambitious launch schedule.
“We have ACQUISITION OF SIGNAL,” the startup tweeted soon after the Falcon 9 launch on June 12. “The world’s first space factory’s solar panels have found the sun and it’s beginning to de-tumble.”
During the satellite’s first week in space, Varda will focus on testing its systems to make sure everything works as hoped. The second week will be dedicated to heating and cooling the old HIV-AIDS drug ritonavir repeatedly to study how its particles crystalize in microgravity.
After about a month in space, Varda will attempt to bring its first space factory back to Earth, sending it through the atmosphere at hypersonic speeds and then using a parachute system to safely land at the Department of Defense’s Utah Test and Training Range.
Looking ahead: Ultimately, Varda’s space factories could end up serving dual purposes as manufacturing facilities and hypersonic testbeds — the Air Force has already awarded the startup a contract to use its next reentry capsule to test hardware for hypersonic missiles.
But as for manufacturing other types of goods, Varda plans to stick with drugs for now.
“[Pharmaceuticals] are the most valuable chemicals per unit mass,” Bruey told CNN. “And they also have a large market on Earth.”
“You’re not going to see Varda do anything other than pharmaceuticals for the next minimum of six, seven years,” added Delian Asparouhov, Varda’s co-founder and president.
Genes that protect health with Dr. Nir Barzilai
In today’s podcast episode, I talk with Nir Barzilai, a geroscientist, which means he studies the biology of aging. Barzilai directs the Institute for Aging Research at the Albert Einstein College of Medicine.
My first question for Dr. Barzilai was: why do we age? And is there anything to be done about it? His answers were encouraging. We can’t live forever, but we have some control over the process, as he argues in his book, Age Later.
Dr. Barzilai told me that centenarians differ from the rest of us because they have unique gene mutations that help them stay healthy longer. For most of us, the words “gene mutations” spell trouble - we associate these words with cancer or neurodegenerative diseases, but apparently not all mutations are bad.
Listen on Apple | Listen on Spotify | Listen on Stitcher | Listen on Amazon | Listen on Google
Centenarians may have essentially won the genetic lottery, but that doesn’t mean the rest of us are predestined to have a specific lifespan and health span, or the amount of time spent living productively and enjoyably. “Aging is a mother of all diseases,” Dr. Barzilai told me. And as a disease, it can be targeted by therapeutics. Dr. Barzilai’s team is already running clinical trials on such therapeutics — and the results are promising.
More about Dr. Barzilai: He is scientific director of AFAR, American Federation for Aging Research. As part of his work, Dr. Barzilai studies families of centenarians and their genetics to learn how the rest of us can learn and benefit from their super-aging. He also organizing a clinical trial to test a specific drug that may slow aging.
Show Links
Age Later: Health Span, Life Span, and the New Science of Longevity https://www.amazon.com/Age-Later-Healthiest-Sharpest-Centenarians/dp/1250230853
American Federation for Aging Research https://www.afar.org
https://www.afar.org/nir-barzilai
https://www.einsteinmed.edu/faculty/484/nir-barzilai/
Metformin as a Tool to Target Aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/
Benefits of Metformin in Attenuating the Hallmarks of Aging https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426/
The Longevity Genes Project https://www.einsteinmed.edu/centers/aging/longevity-genes-project/
Lina Zeldovich has written about science, medicine and technology for Popular Science, Smithsonian, National Geographic, Scientific American, Reader’s Digest, the New York Times and other major national and international publications. A Columbia J-School alumna, she has won several awards for her stories, including the ASJA Crisis Coverage Award for Covid reporting, and has been a contributing editor at Nautilus Magazine. In 2021, Zeldovich released her first book, The Other Dark Matter, published by the University of Chicago Press, about the science and business of turning waste into wealth and health. You can find her on http://linazeldovich.com/ and @linazeldovich.