Is Alzheimer's Research On the Wrong Track?
Scientist in laboratory
"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."
Here's how one doctor overcame extraordinary odds to help create the birth control pill
Dr. Percy Julian had so many personal and professional obstacles throughout his life, it’s amazing he was able to accomplish anything at all. But this hidden figure not only overcame these incredible obstacles, he also laid the foundation for the creation of the birth control pill.
Julian’s first obstacle was growing up in the Jim Crow-era south in the early part of the twentieth century, where racial segregation kept many African-Americans out of schools, libraries, parks, restaurants, and more. Despite limited opportunities and education, Julian was accepted to DePauw University in Indiana, where he majored in chemistry. But in college, Julian encountered another obstacle: he wasn’t allowed to stay in DePauw’s student housing because of segregation. Julian found lodging in an off-campus boarding house that refused to serve him meals. To pay for his room, board, and food, Julian waited tables and fired furnaces while he studied chemistry full-time. Incredibly, he graduated in 1920 as valedictorian of his class.
After graduation, Julian landed a fellowship at Harvard University to study chemistry—but here, Julian ran into yet another obstacle. Harvard thought that white students would resent being taught by Julian, an African-American man, so they withdrew his teaching assistantship. Julian instead decided to complete his PhD at the University of Vienna in Austria. When he did, he became one of the first African Americans to ever receive a PhD in chemistry.
Julian received offers for professorships, fellowships, and jobs throughout the 1930s, due to his impressive qualifications—but these offers were almost always revoked when schools or potential employers found out Julian was black. In one instance, Julian was offered a job at the Institute of Paper Chemistory in Appleton, Wisconsin—but Appleton, like many cities in the United States at the time, was known as a “sundown town,” which meant that black people weren’t allowed to be there after dark. As a result, Julian lost the job.
During this time, Julian became an expert at synthesis, which is the process of turning one substance into another through a series of planned chemical reactions. Julian synthesized a plant compound called physostigmine, which would later become a treatment for an eye disease called glaucoma.
In 1936, Julian was finally able to land—and keep—a job at Glidden, and there he found a way to extract soybean protein. This was used to produce a fire-retardant foam used in fire extinguishers to smother oil and gasoline fires aboard ships and aircraft carriers, and it ended up saving the lives of thousands of soldiers during World War II.
At Glidden, Julian found a way to synthesize human sex hormones such as progesterone, estrogen, and testosterone, from plants. This was a hugely profitable discovery for his company—but it also meant that clinicians now had huge quantities of these hormones, making hormone therapy cheaper and easier to come by. His work also laid the foundation for the creation of hormonal birth control: Without the ability to synthesize these hormones, hormonal birth control would not exist.
Julian left Glidden in the 1950s and formed his own company, called Julian Laboratories, outside of Chicago, where he manufactured steroids and conducted his own research. The company turned profitable within a year, but even so Julian’s obstacles weren’t over. In 1950 and 1951, Julian’s home was firebombed and attacked with dynamite, with his family inside. Julian often had to sit out on the front porch of his home with a shotgun to protect his family from violence.
But despite years of racism and violence, Julian’s story has a happy ending. Julian’s family was eventually welcomed into the neighborhood and protected from future attacks (Julian’s daughter lives there to this day). Julian then became one of the country’s first black millionaires when he sold his company in the 1960s.
When Julian passed away at the age of 76, he had more than 130 chemical patents to his name and left behind a body of work that benefits people to this day.
Therapies for Healthy Aging with Dr. Alexandra Bause
My guest today is Dr. Alexandra Bause, a biologist who has dedicated her career to advancing health, medicine and healthier human lifespans. Dr. Bause co-founded a company called Apollo Health Ventures in 2017. Currently a venture partner at Apollo, she's immersed in the discoveries underway in Apollo’s Venture Lab while the company focuses on assembling a team of investors to support progress. Dr. Bause and Apollo Health Ventures say that biotech is at “an inflection point” and is set to become a driver of important change and economic value.
Previously, Dr. Bause worked at the Boston Consulting Group in its healthcare practice specializing in biopharma strategy, among other priorities
She did her PhD studies at Harvard Medical School focusing on molecular mechanisms that contribute to cellular aging, and she’s also a trained pharmacist
In the episode, we talk about the present and future of therapeutics that could increase people’s spans of health, the benefits of certain lifestyle practice, the best use of electronic wearables for these purposes, and much more.
Dr. Bause is at the forefront of developing interventions that target the aging process with the aim of ensuring that all of us can have healthier, more productive lifespans.
