Is Alzheimer's Research On the Wrong Track?

Scientist in laboratory

(© kkolosov / Fotolia)


"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."

Linda Marsa
Linda Marsa is a contributing editor at Discover, a former Los Angeles Times reporter and author of Fevered: Why a Hotter Planet Will Harm Our Health and How We Can Save Ourselves (Rodale, 2013), which the New York Times called “gripping to read.” Her work has been anthologized in The Best American Science Writing, and she has written for numerous publications, including Newsweek, U.S. News & World Report, Nautilus, Men’s Journal, Playboy, Pacific Standard and Aeon.
Get our top stories twice a month
Follow us on

On the left, a Hermès bag made using fine mycelium as a leather alternative, made in partnership with the biotech company MycoWorks; on right, a sheet of mycelium "leather."

Photo credit: Coppi Barbieri and MycoWorks

A natural material that looks and feels like real leather is taking the fashion world by storm. Scientists view mycelium—the vegetative part of a mushroom-producing fungus—as a planet-friendly alternative to animal hides and plastics.

Products crafted from this vegan leather are emerging, with others poised to hit the market soon. Among them are the Hermès Victoria bag, Lululemon's yoga accessories, Adidas' Stan Smith Mylo sneaker, and a Stella McCartney apparel collection.

Keep Reading Keep Reading
Susan Kreimer
Susan Kreimer is a New York-based freelance journalist who has followed the landscape of health care since the late 1990s, initially as a staff reporter for major daily newspapers. She writes about breakthrough studies, personal health, and the business of clinical practice. Raised in the Chicago area, she holds a B.A. in Journalism/Mass Communication and French from the University of Iowa and an M.S. from the Columbia University Graduate School of Journalism.

From a special food to a vaccine and gene editing, new technologies may offer solutions for cat lovers with allergies.

Photo by Pacto Visual on Unsplash

Amy Bitterman, who teaches at Rutgers Law School in Newark, gets enormous pleasure from her three mixed-breed rescue cats, Spike, Dee, and Lucy. To manage her chronically stuffy nose, three times a week she takes Allegra D, which combines the antihistamine fexofenadine with the decongestant pseudoephedrine. Amy's dog allergy is rougher--so severe that when her sister launched a business, Pet Care By Susan, from their home in Edison, New Jersey, they knew Susan would have to move elsewhere before she could board dogs. Amy has tried to visit their brother, who owns a Labrador Retriever, taking Allegra D beforehand. But she began sneezing, and then developed watery eyes and phlegm in her chest.

"It gets harder and harder to breathe," she says.

Animal lovers have long dreamed of "hypo-allergenic" cats and dogs. Although to date, there is no such thing, biotechnology is beginning to provide solutions for cat-lovers. Cats are a simpler challenge than dogs. Dog allergies involve as many as seven proteins. But up to 95 percent of people who have cat allergies--estimated at 10 to 30 percent of the population in North America and Europe--react to one protein, Fel d1. Interestingly, cats don't seem to need Fel d1. There are cats who don't produce much Fel d1 and have no known health problems.

Keep Reading Keep Reading
Temma Ehrenfeld
Temma Ehrenfeld writes about health and psychology. In a previous life, she was a reporter and editor at Newsweek and Fortune. You can see more of her work at her writing portfolio (https://temmaehrenfeld.contently.com) and contact her through her Psychology Today blog.