Scientists are coming around to a surprising new understanding of Alzheimer's disease, and it could supercharge drug development for the $1.1 trillion problem

• Caring for patients with Alzheimer’s disease is expected to cost $1.1 trillion in the U.S. by 2050.
• Hopes for a universal treatment are dwindling after 146 experimental drugs failed in human trials.
• New genetic insights are upending the way scientists approach Alzheimer’s.
• See more stories on Insider’s business page.

In January, at the World Economic Forum’s annual gathering of some of the globe’s richest and most powerful leaders, Andrea Pfeifer was promoting her biotech company and a new global initiative to treat Alzheimer’s.

During a Q&A session, George Vradenburg, the entertainment lawyer turned philanthropist, asked her a question about her work: “Is Alzheimer’s not one disease?”

“It’s definitely not one disease,” she replied.

That theory has been floating around for years, creating some controversy among neuroscientists. But Pfeifer, the chief executive of the small biotech AC Immune, said that when she declared her view of Alzheimer’s during the virtual meeting, the audience was receptive.

Alzheimer’s has been creeping up on countries across the globe like a slow pandemic. And it’s sinking in that researchers, financiers, and world leaders need to completely change the way they approach creating treatments.

The once controversial idea that Alzheimer’s is in fact a highly varied disease, if not multiple distinct but related conditions, is gaining traction and could unlock new approaches to treating it. Drugmakers are formulating their clinical trials differently, and even the National Institutes of Health is changing how it funds research.

Alzheimer’s disease looms as a major global health crises. It affects as many as 35 million people worldwide — a figure that’s expected to triple by 2050 as the world’s population ages. In the US alone, caring for these patients is expected to cost $1.1 trillion annually by that time.

Learning from cancer to treat Alzheimer’s

There are five drugs available for people with Alzheimer’s. But they can’t stop or reverse the disease, and they aren’t particularly good at stemming memory loss. As scientists and drug companies search for a way to stop the disease, they’ve uncovered new details about the brain disorder, including around 100 genes that play a role.

In essence, doctors and scientists are increasingly coming around to the idea that Alzheimer’s may be more like cancer — an array of related, yet distinct, maladies that could require a number of different treatments.

That means the road map for treating Alzheimer’s could be similar to what the drug industry has done to treat cancer, a half dozen biotech founders and executives told Insider. Researchers are homing in on the genetic signatures of the disorders to come up with new, targeted treatments.

It took about 35 to 40 years to crack this code in cancer. And while cancer is far from being cured, many forms of the disease can now be treated effectively. Research into the genetics of Alzheimer’s is in its fourth decade, meaning that new, promising therapies could come by 2030.

Amyloid beta: Scientists focus on the insidious brain protein

For more than a decade, the conversation around treating Alzheimer’s has started with two words: amyloid beta.

The insidious protein builds up in the brains of most Alzheimer’s patients. It’s one of the few tangible, unifying factors that offered a strategy for treating the majority of patients — get rid of the amyloid beta, and surely the symptoms of Alzheimer’s disease would disappear along with it, scientists thought.

Drug companies had further incentive to focus on amyloid once scientists developed a better way to monitor the plaques using PET imaging. Before that, it had been impossible to spot the protein without cutting into a person’s brain after death. Now, researchers can simply scan a person’s head to see how amyloid spreads and grows.

The tools were all there, so scientists glommed on to the so-called amyloid theory. But time and time again, clearing the plaque has failed to stop the erosion of memory and cognitive functions in trials with thousands of patients.

Biogen’s aducanumab, which is being reviewed by the FDA, and Eli Lilly’s donanemab — drugs designed to treat the amyloid buildup — have shown a glimmer of hope with specific groups of Alzheimer’s patients. Aducanumab seemed to work best, but caused more side effects, in people with a gene linked to the disease, APOE4.

Dividing Alzheimer’s patients into subgroups would cut down on the revenue potential for a single product such as aducanumab.

Still, it could be a blockbuster drug if approved by the FDA this spring, Stifel analyst Paul Matteis said, but it would likely make a few billion dollars a year in sales, not the tens of billions of dollars some analysts had predicted.

Howard Fillit, the executive director of the Alzheimer’s Drug Discovery Foundation in New York, said he thinks there’s merit to the amyloid hypothesis, but that it may not be enough for all patients.

“Most of us think we’re ultimately going to need more than one drug, targeting more than one pathway,” he said.

Rudy Tanzi, a professor at Harvard University, has studied Alzheimer’s disease for decades.Paul Morigi/Getty ImagesDecoding the genes linked to Alzheimer’s

Amyloid certainly plays an important role in Alzheimer’s — Rudy Tanzi, a professor at Harvard University, likens it to a spark that sets off a forest fire in the brain.

But it’s just one element of the disease that drugmakers should be investigating, Tanzi said. There are other biological changes that occur in the brain as the disease progresses, and genetic mutations that seem to feed the flames.

Extinguishing those flames is all about using the right drug at the right time, Tanzi said.

Tanzi, a neurologist by training, has led many efforts to decode Alzheimer’s. He helped identify many of the genes linked to the disease and created three-dimensional human brain cells in petri dishes to show how amyloid goes haywire in Alzheimer’s patients.

As Alzheimer’s disease progresses, another protein called tau accumulates in long threads that get tangled around the brain’s communication pathways. Neurons, the cells that transmit information and connect different parts of the brain, stop functioning and die off. This flurry of dying cells prompts the immune system to kick in, but research showed it may be malfunctioning in Alzheimer’s disease.

Genetics can help drugmakers determine where to step in.

Some Alzheimer’s patients have genes that are linked to amyloid production, while others are tied to tau. Around 30 are tied to the microglia — immune cells that live specifically in the nervous system, patrolling and cleaning up toxic proteins and damaged cells.

For patients with a genetic mutation that causes the microglia to malfunction, a medication focused on decreasing the buildup of amyloid may not be effective, for example.

Alzheimer’s could be related to other brain disorders

As they dig deeper into the genetics of Alzheimer’s, researchers working in academic and biopharmaceutical laboratories are coalescing around an idea: The disease constellation that we call Alzheimer’s has connections to other debilitating brain disorders.

In March, a team of 100 specialists, including the NIH researcher Sonja Scholz, published a paper detailing five genes that are common across Alzheimer’s, Parkinson’s, and Lewy body dementia.

The diseases vary in how they affect patients — Parkinson’s primarily affects movement, not memory, while Lewy body dementia can cause hallucinations and dizziness. Scholz’s theory is that all three lie on a disease spectrum.

The findings are especially significant because the National Institutes of Health, which is the single largest funder of medical research, has long separated Alzheimer’s from other neurological diseases.

For decades, Alzheimer’s work and grants have been overseen by the NIH’s Institute on Aging, while work on conditions such as Parkinson’s disease, Lou Gehrig’s disease, and even other forms of dementia fell under a separate arm of the organization. It’s just in the last couple of years that the two branches have begun teaming up.

Finding common threads between Alzheimer’s and other diseases could also create more opportunities for the small biotechs propelling treatment options forward. These companies often have limited budgets — venture-capital firms aren’t keen on financing work on Alzheimer’s disease after 146 treatments failed in clinical trials over the last two decades.

The idea that there are common threads between neurological diseases has resonated with  philanthropists and changed the tone of licensing conversations with drug companies, said Dr. Steve Finkbeiner, the director of Alzheimer’s disease and neuroscience research at the Gladstone Institutes. Finkbeiner began looking at connections between these brain disorders about nine years ago.

“When we had conversations with drug companies, it was a lot easier, because if we could say that this small molecule drug or whatever worked in multiple models, they’d say, “Wow, maybe it’s a little less risky,'” he said.

Scientists switch strategies in treating Alzheimer’s

In San Francisco, the startup Denali Therapeutics is developing a medication for a protein called RIPK1 that acts as a traffic light, signaling immune cells to clean up toxic proteins and defend against pathogens. The hope is that regulating this protein may stop immune cells from damaging the brain’s memory centers.

The startup is applying this approach not only to Alzheimer’s but also to ALS and multiple sclerosis. The Denali team’s interest in how RIPK1 played a role in Alzheimer’s disease drove the work, Carole Ho, the chief medical officer, said. But being able to apply that type of treatment to three diseases is what makes it a decent financial bet.

It echoes the strategy of game-changing cancer drugs such as Merck’s Keytruda, which catalyzes immune cells to attack cancer cells. Merck started small with Keytruda, first getting it approved by the FDA as a treatment for melanoma patients with a certain type of genetic mutation. Then, Merck expanded the drug’s use repeatedly over the last seven years. Keytruda now brings in $14.4 billion annually and is expected to keep grabbing more of the cancer market.

Trials of this size are expensive — they can easily cost $300 million, Pfeifer said. The US Food and Drug Administration generally requires not one but two of these tests for approval.

Now, the remaining crenezumab trial is being led by the Alzheimer’s Prevention Initiative and focuses on a small group of people with a mutation in the PSEN1 gene — one of the three genes known to cause Alzheimer’s. It’s been estimated that the PSEN1 mutation affects around 5,000 people in one area of Colombia. Data from this trial is expected next year, and would show the scientific community if homing in on smaller, more homogenous groups of patients could make drug development more feasible.

Starting small goes against the grain of what Alzheimer’s drugmakers have attempted to do over the past decade, said Ken Rhodes, who was involved in the early development of Biogen’s Alzheimer’s drug aducanumab. Rhodes joined Biogen as the vice president of neurology in 2007, the same year that the biotech licensed the foundational antibody science used in the drug.

“Maybe if we’d done it the other way around, we’d be in a different place now. But, you know, we didn’t know as much about the genetics when those programs started,” he said, referring to amyloid-targeting drugs such as aducanumab.

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