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."
Telehealth offers a vast improvement in access and convenience to all sorts of medical services, and online therapy for mental health is one of the most promising case studies for telehealth. With many online therapy options available, you can choose whatever works best for you. Yet many people are hesitant about using online therapy. Even if they do give it a try, they often don’t know how to make the most effective use of this treatment modality.
Why do so many feel uncertain about online therapy? A major reason stems from its novelty. Humans are creatures of habit, prone to falling for what behavioral scientists like myself call the status quo bias, a predisposition to stick to traditional practices and behaviors. Many people reject innovative solutions even when they would be helpful. Thus, while teletherapy was available long before the pandemic, and might have fit the needs of many potential clients, relatively few took advantage of this option.
Even when we do try new methodologies, we often don’t do so effectively, because we cling to the same approaches that worked in previous situations. Scientists call this behavior functional fixedness. It’s kind of like the saying about the hammer-nail syndrome: “when you have a hammer, everything looks like a nail.”
These two mental blindspots, the status quo bias and functional fixedness, impact decision making in many areas of life. Fortunately, recent research has shown effective and pragmatic strategies to defeat these dangerous errors in judgment. The nine tips below will help you make the best decisions to get effective online therapy, based on the latest research.
For instance, a 2014 study in the Journal of Affective Disorders reported that online treatment proved just as effective as face-to-face treatment for depression. A 2018 study, published in Journal of Psychological Disorders, found that online cognitive behavioral therapy, or CBT, was just as effective as face-to-face treatment for major depression, panic disorder, social anxiety disorder, and generalized anxiety disorder. And a 2014 study in Behaviour Research and Therapy discovered that online CBT proved effective in treating anxiety disorders, and helped lower costs of treatment.
During the forced teletherapy of COVID, therapists worried that those with serious mental health conditions would be less likely to convert to teletherapy. Yet research published in Counselling Psychology Quarterly has helped to alleviate that concern. It found that those with schizophrenia, bipolar disorder, severe depression, PTSD, and even suicidality converted to teletherapy at about the same rate as those with less severe mental health challenges.
Yet teletherapy may not be for everyone. For example, adolescents had the most varied response to teletherapy, according to a 2020 study in Family Process. Some adapted quickly and easily, while others found it awkward and anxiety-inducing. On the whole, children with trauma respond worse to online therapy, per a 2020 study in Child Abuse & Neglect. The treatment of mental health issues can sometimes require in-person interactions, such as the use of eye movement desensitization and reprocessing to treat post-traumatic stress disorder. And according to a 2020 study from the Journal of Humanistic Psychology, online therapy may not be as effective for those suffering from loneliness.
Online therapy is much more accessible than in-person therapy for those with a decent internet connection, webcam, mic, and digital skills. You don’t have to commute to your therapist’s office, wasting money and time. You can take much less medical leave from work, saving you money and hassle with your boss. If you live in a sparsely populated area, online therapy could allow you to access many specialized kinds of therapy that isn’t accessible locally.
Online options are much quicker compared to the long waiting lines for in-person therapy. You also have much more convenient scheduling options. And you won’t have to worry about running into someone you know in the waiting room. Online therapy is easier to conceal from others and reduces stigma. Many patients may feel more comfortable and open to sharing in the privacy and comfort of their own home.
You can use a variety of communication tools suited to your needs at any given time. Video can be used to start a relationship with a therapist and have more intense and nuanced discussions, but can be draining, especially for those with social anxiety. Voice-only may work well for less intense discussions. Email offers a useful option for long-form, well-thought-out messages. Texting is useful for quick, real-time questions, answers, and reinforcement.
Plus, online therapy is often cheaper than in-person therapy. In the midst of COVID, many insurance providers have decided to cover online therapy.
One weakness is the requirement for appropriate technology and skills to engage in online therapy. Another is the difficulty of forming a close therapeutic relationship with your therapist. You won’t be able to communicate non-verbals as fully and the therapist will not be able to read you as well, requiring you to be more deliberate in how you express yourself.
Another important issue is that online therapy is subject to less government oversight compared to the in-person approach, which is regulated in each state, providing a baseline of quality control. As a result, you have to do more research on the providers that offer online therapy to make sure they’re reputable, use only licensed therapists, and have a clear and transparent pay structure.
Figure out what kind of goals you want to achieve. Consider how, within the context of your goals, you can leverage the benefits of online therapy while addressing the weaknesses. Write down and commit to achieving your goals. Remember, you need to be your own advocate, especially in the less regulated space of online therapy, so focus on being proactive in achieving your goals.
Because online therapy can occur at various times of day through videos calls, emails and text, it might feel more open-ended and less organized, which can have advantages and disadvantages. One way you can give it more structure is to ground these interactions in the story of your self-improvement. Our minds perceive the world through narratives. Create a story of how you’ll get from where you are to where you want to go, meaning your goals.
A good template to use is the Hero’s Journey. Start the narrative with where you are, and what caused you to seek therapy. Write about the obstacles you will need to overcome, and the kind of help from a therapist that you’ll need in the process. Then, describe the final end state: how will you be better off after this journey, including what you will have learned.
Especially in online therapy, you need to be on top of things. Too many people let the therapist manage the treatment plan. As you pursue your hero’s journey, another way to organize for success is to take notes on your progress, and reevaluate how you’re doing every month with your therapist.
Since it’s more difficult to be confident about the quality of service providers in an online setting, you should identify in advance the traits of your desired therapist. Every Hero’s Journey involves a mentor figure who guides the protagonist through this journey. So who’s your ideal mentor? Write out their top 10 characteristics, from most to least important.
For example, you might want someone who is:
- Good listener
That’s my list. Depending on what challenge you’re facing and your personality and preferences, you should make your own. Then, when you are matched with a therapist, evaluate how well they fit your ideal list.
When you first match with a therapist, try to fail fast. That means, instead of focusing on getting treatment, focus on figuring out if the therapist is a good match based on the traits you identified above. That will enable you to move on quickly if they’re not, and it’s very much worth it to figure that out early.
Tell them your goals, your story, and your vision of your ideal mentor. Ask them whether they think they are a match, and what kind of a treatment plan they would suggest based on the information you provided. And observe them yourself in your initial interactions, focusing on whether they’re a good match. Often, you’ll find that your initial vision of your ideal mentor is incomplete, and you’ll learn through doing therapy what kind of a therapist is the best fit for you.
This small subgoal should be sufficient to be meaningful and impactful for improving your mental health, but not a big stretch for you to achieve. This subgoal should be a tool for you to use to evaluate whether the therapist is indeed a good fit for you. It will also help you evaluate whether the treatment plan makes sense, or whether it needs to be revised.
As you approach the end of your planned work and you see you’re reaching your goals, talk to the therapist about how to wrap up rather than letting things drag on for too long. You don’t want to become dependent on therapy: it’s meant to be a temporary intervention. Some less scrupulous therapists will insist that therapy should never end and we should all stay in therapy forever, and you want to avoid falling for this line. When you reach your goals, end your therapy, unless you discover a serious new reason to continue it. Still, it may be wise to set up occasional check-ins once every three to six months to make sure you’re staying on the right track.
This is part 2 of a three part series on a new generation of doctors leading the charge to make the health care industry more sustainable - for the benefit of their patients and the planet. Read part 1 here.
After graduating from her studies as an engineer, Nora Stroetzel ticked off the top item on her bucket list and traveled the world for a year. She loved remote places like the Indonesian rain forest she reached only by hiking for several days on foot, mountain villages in the Himalayas, and diving at reefs that were only accessible by local fishing boats.
“But no matter how far from civilization I ventured, one thing was already there: plastic,” Stroetzel says. “Plastic that would stay there for centuries, on 12,000 foot peaks and on beaches several hundred miles from the nearest city.” She saw “wild orangutans that could be lured by rustling plastic and hermit crabs that used plastic lids as dwellings instead of shells.”
While traveling she started volunteering for beach cleanups and helped build a recycling station in Indonesia. But the pivotal moment for her came after she returned to her hometown Kiel in Germany. “At the dentist, they gave me a plastic cup to rinse my mouth. I used it for maybe ten seconds before it was tossed out,” Stroetzel says. “That made me really angry.”
She decided to research alternatives for plastic in the medical sector and learned that cups could be reused and easily disinfected. All dentists routinely disinfect their tools anyway and, Stroetzel reasoned, it wouldn’t be too hard to extend that practice to cups.
It's a good example for how often plastic is used unnecessarily in medical practice, she says. The health care sector is the fifth biggest source of pollution and trash in industrialized countries. In the U.S., hospitals generate an estimated 6,000 tons of waste per day, including an average of 400 grams of plastic per patient per day, and this sector produces 8.5 percent of greenhouse gas emissions nationwide.
“Sustainable alternatives exist,” Stroetzel says, “but you have to painstakingly look for them; they are often not offered by the big manufacturers, and all of this takes way too much time [that] medical staff simply does not have during their hectic days.”
When Stroetzel spoke with medical staff in Germany, she found they were often frustrated by all of this waste, especially as they took care to avoid single-use plastic at home. Doctors in other countries share this frustration. In a recent poll, nine out of ten doctors in Germany said they’re aware of the urgency to find sustainable solutions in the health industry but don’t know how to achieve this goal.
After a year of researching more sustainable alternatives, Stroetzel founded a social enterprise startup called POP, short for Practice Without Plastic, together with IT expert Nicolai Niethe, to offer well-researched solutions. “Sustainable alternatives exist,” she says, “but you have to painstakingly look for them; they are often not offered by the big manufacturers, and all of this takes way too much time [that] medical staff simply does not have during their hectic days.”
In addition to reusable dentist cups, other good options for the heath care sector include washable N95 face masks and gloves made from nitrile, which waste less water and energy in their production. But Stroetzel admits that truly making a medical facility more sustainable is a complex task. “This includes negotiating with manufacturers who often package medical materials in double and triple layers of extra plastic.”
While initiatives such as Stroetzel’s provide much needed information, other experts reason that a wholesale rethinking of healthcare is needed. Voluntary action won’t be enough, and government should set the right example. Kari Nadeau, a Stanford physician who has spent 30 years researching the effects of environmental pollution on the immune system, and Kenneth Kizer, the former undersecretary for health in the U.S. Department of Veterans Affairs, wrote in JAMA last year that the medical industry and federal agencies that provide health care should be required to measure and make public their carbon footprints. “Government health systems do not disclose these data (and very rarely do private health care organizations), unlike more than 90% of the Standard & Poor’s top 500 companies and many nongovernment entities," they explained. "This could constitute a substantial step toward better equipping health professionals to confront climate change and other planetary health problems.”
Compared to the U.K., the U.S. healthcare industry lags behind in terms of measuring and managing its carbon footprint, and hospitals are the second highest energy user of any sector in the U.S.
Kizer and Nadeau look to the U.K. National Health Service (NHS), which created a Sustainable Development Unit in 2008 and began that year to conduct assessments of the NHS’s carbon footprint. The NHS also identified its biggest culprits: Of the 2019 footprint, with emissions totaling 25 megatons of carbon dioxide equivalent, 62 percent came from the supply chain, 24 percent from the direct delivery of care, 10 percent from staff commute and patient and visitor travel, and 4 percent from private health and care services commissioned by the NHS. From 1990 to 2019, the NHS has reduced its emission of carbon dioxide equivalents by 26 percent, mostly due to the switch to renewable energy for heat and power. Meanwhile, the NHS has encouraged health clinics in the U.K. to install wind generators or photovoltaics that convert light to electricity -- relatively quick ways to decarbonize buildings in the health sector.
Compared to the U.K., the U.S. healthcare industry lags behind in terms of measuring and managing its carbon footprint, and hospitals are the second highest energy user of any sector in the U.S. “We are already seeing patients with symptoms from climate change, such as worsened respiratory symptoms from increased wildfires and poor air quality in California,” write Thomas B. Newman, a pediatrist at the University of California, San Francisco, and UCSF clinical research coordinator Daisy Valdivieso. “Because of the enormous health threat posed by climate change, health professionals should mobilize support for climate mitigation and adaptation efforts.” They believe “the most direct place to start is to approach the low-lying fruit: reducing healthcare waste and overuse.”
In addition to resulting in waste, the plastic in hospitals ultimately harms patients, who may be even more vulnerable to the effects due to their health conditions. Microplastics have been detected in most humans, and on average, a human ingests five grams of microplastic per week. Newman and Valdivieso refer to the American Board of Internal Medicine's Choosing Wisely program as one of many initiatives that identify and publicize options for “safely doing less” as a strategy to reduce unnecessary healthcare practices, and in turn, reduce cost, resource use, and ultimately reduce medical harm.
A few U.S. clinics are pioneers in transitioning to clean energy sources. In Wisconsin, the nonprofit Gundersen Health network became the first hospital to cut its reliance on petroleum by switching to locally produced green energy in 2015, and it saved $1.2 million per year in the process. Kaiser Permanente eliminated its 800,000 ton carbon footprint through energy efficiency and purchasing carbon offsets, reaching a balance between carbon emissions and removing carbon from the atmosphere in 2020, the first U.S. health system to do so.
Cleveland Clinic has pledged to join Kaiser in becoming carbon neutral by 2027. Realizing that 80 percent of its 2008 carbon emissions came from electricity consumption, the Clinic started switching to renewable energy and installing solar panels, and it has invested in researching recyclable products and packaging. The Clinic’s sustainability report outlines several strategies for producing less waste, such as reusing cases for sterilizing instruments, cutting back on materials that can’t be recycled, and putting pressure on vendors to reduce product packaging.
The Charité Berlin, Europe’s biggest university hospital, has also announced its goal to become carbon neutral. Its sustainability managers have begun to identify the biggest carbon culprits in its operations. “We’ve already reduced CO2 emissions by 21 percent since 2016,” says Simon Batt-Nauerz, the director of infrastructure and sustainability.
The hospital still emits 100,000 tons of CO2 every year, as much as a city with 10,000 residents, but it’s making progress through ride share and bicycle programs for its staff of 20,000 employees, who can get their bikes repaired for free in one of the Charité-operated bike workshops. Another program targets doctors’ and nurses’ scrubs, which cause more than 200 tons of CO2 during manufacturing and cleaning. The staff is currently testing lighter, more sustainable scrubs made from recycled cellulose that is grown regionally and requires 80 percent less land use and 30 percent less water.
The Charité hospital in Berlin still emits 100,000 tons of CO2 every year, but it’s making progress through ride share and bicycle programs for its staff of 20,000 employees.
Wiebke Peitz | Specific to Charité
Anesthesiologist Susanne Koch spearheads sustainability efforts in anesthesiology at the Charité. She says that up to a third of hospital waste comes from surgery rooms. To reduce medical waste, she recommends what she calls the 5 Rs: Reduce, Reuse, Recycle, Rethink, Research. “In medicine, people don’t question the use of plastic because of safety concerns,” she says. “Nobody wants to be sued because something is reused. However, it is possible to reduce plastic and other materials safely.”
For instance, she says, typical surgery kits are single-use and contain more supplies than are actually needed, and the entire kit is routinely thrown out after the surgery. “Up to 20 percent of materials in a surgery room aren’t used but will be discarded,” Koch says. One solution could be smaller kits, she explains, and another would be to recycle the plastic. Another example is breathing tubes. “When they became scarce during the pandemic, studies showed that they can be used seven days instead of 24 hours without increased bacteria load when we change the filters regularly,” Koch says, and wonders, “What else can we reuse?”
In the Netherlands, TU Delft researchers Tim Horeman and Bart van Straten designed a method to melt down the blue polypropylene wrapping paper that keeps medical instruments sterile, so that the material can be turned it into new medical devices. Currently, more than a million kilos of the blue paper are used in Dutch hospitals every year. A growing number of Dutch hospitals are adopting this approach.
Another common practice that’s ripe for improvement is the use of a certain plastic, called PVC, in hospital equipment such as blood bags, tubes and masks. Because of its toxic components, PVC is almost never recycled in the U.S., but University of Michigan researchers Danielle Fagnani and Anne McNeil have discovered a chemical process that can break it down into material that could be incorporated back into production. This could be a step toward a circular economy “that accounts for resource inputs and emissions throughout a product’s life cycle, including extraction of raw materials, manufacturing, transport, use and reuse, and disposal,” as medical experts have proposed. “It’s a failure of humanity to have created these amazing materials which have improved our lives in many ways, but at the same time to be so shortsighted that we didn’t think about what to do with the waste,” McNeil said in a press release.
Susanne Koch puts it more succinctly: “What’s the point if we save patients while killing the planet?”