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Alzheimer’s Is More Complicated Than We Thought
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Alzheimer’s Is More Complicated Than We Thought

With a much-needed spike in research funding, scientists are transcending a one-size-fits-all approach for the disease and looking at personalized strategies for prevention and treatment.

W hen Dr. Roberta Diaz Brinton first theorized that people with Alzheimer’s disease could grow back the brain cells they’d lost, almost nobody believed her. It was the late 1980s, and Dr. Brinton sought funding to investigate whether the drug allopregnanolone—a naturally occurring brain steroid—could promote a process called neurogenesis, which triggers brain cell growth and might restore cognitive function. But the idea was “a bit too bold” for scientific grant reviewers. She failed to attract research dollars, so she moved on to other areas of Alzheimer’s research. “I literally put that idea away for 10 years,” she says.

Now, at the University of Arizona’s Center for Innovation in Brain Science, Dr. Brinton is finally putting her hypothesis to the test in a Phase 2a clinical trial, which is funded in part by a $1 million grant from the Alzheimer’s Association’s Part the Cloud Initiative and an award from the National Institute on Aging (NIA), part of the National Institutes of Health (NIH). While the trial is currently on pause due to the COVID-19 pandemic, Dr. Brinton is eager to resume the work so she can determine whether the drug is safe and effective when administered through muscular injections. If the results are good, she’ll be one step closer to bringing the world’s first regenerative therapeutic for Alzheimer’s to the millions of people living with the disease.

Early Discoveries

German physician Dr. Alois Alzheimer discovered Alzheimer’s disease in 1906, but it took decades for researchers to pinpoint the two hallmarks of the disorder. In 1984, George Glenner and Cai’ne Wong found that Alzheimer’s brain plaques are formed when beta-amyloid protein pieces clump together. Two years later, researchers discovered that the tau protein is a key component of tangles, which cause nerve cells to die.

Amyloid Plaques

Tau Protein Tangles

Alzheimer's Affected Neuron

It’s one sign of a remarkable reversal of fortune in a field that, just a few decades ago, was barely on the national radar. In the mid-1980s, researchers discovered the two hallmarks of the disease: the accumulation of beta-amyloid plaques in the brain, followed by the appearance of tau protein tangles. But before President Ronald Reagan disclosed his diagnosis in 1994, many members of the public mistakenly believed Alzheimer’s was simply a natural part of aging.

During those years, research dollars for Alzheimer’s and other dementias were scarce. As a result, the clinical trials that received the most funding largely focused on the most established strategy of fighting the disease: clearing plaques—and, to a lesser extent, tangles—from the brain. “Reviewers who were looking at grant applications were incredibly conservative because they had so few dollars to spend,” says Maria Carrillo, PhD, the Alzheimer’s Association’s chief science officer. “So they funded the sure thing. They funded what they knew. They funded what had shown some promise.”

The seemingly safe bets, however, yielded disappointing results. Between 1993 and 2003, the U.S. Food and Drug Administration approved just five drugs to treat Alzheimer’s symptoms, and only one—a combination of two previously-approved drugs—has been approved since. Meanwhile, the disease’s devastating impact on American lives escalated: Between 2000 and 2018, the number of Americans who died each year from Alzheimer’s rose 146 percent. “We didn’t have any more time for safe bets,” says Michaela (Mikey) Hoag, a philanthropist who lost both her parents to the disease. “What we’d been doing the last 10 years wasn’t enough.”

The Prevailing Strategy

For decades, researchers largely focused on one method for fighting the disease: clearing the brain of plaques and tangles. Today, two classes of drugs—Cholinesterase inhibitors and Mematine—are available to treat Alzheimer’s symptoms, but neither have been able to stop the disease itself.

Memantine

Cholinesterase

To better understand the disease and develop more multifaceted treatments, Hoag figured, the scope of research needed to expand. But with limited federal research funds, progress was slow. “The funding was just stuck in the mud at $480 million,” says Hoag. “To move the disease forward in research, we knew the country would have to get to $2 billion.” That’s why, in 2012, Hoag founded Part the Cloud, a philanthropic program designed to speedily get promising treatments into early clinical trials. Over the past eight years, it has awarded $30 million to the kind of unconventional research like Dr. Brinton’s that had long gone overlooked. At the same time, the Alzheimer’s Association advocated for the federal government to increase research funding. Since the 2011 passage of the National Alzheimer’s Project Act, which the Alzheimer’s Association championed, federal research funding for Alzheimer’s and dementia has increased six-fold. This year, the National Institutes of Health will spend an estimated $2.8 billion on research for Alzheimer’s and other dementias. “It has been transformative—completely and totally transformative,” Dr. Brinton says of the funding.

Dr. Brinton’s neurogenesis trial is emblematic of the groundbreaking work becoming far more common in a research field experiencing unprecedented investment and exponential innovation. Today, Alzheimer’s experts say their understanding of the disease’s biology is increasingly complex, and the potential avenues for treatment are more diverse than they’ve ever been. “The field is ready. The world is ready. Our science is ready to embrace the bold,” says Dr. Brinton.

Today, researchers have more resources than ever to explore a wide range of processes that contribute to the disease—including neuroinflammation, immune response, cell signaling and communication, and metabolic function. Many of those processes, researchers have discovered, start happening inside the brain decades before the onset of symptoms, which has changed the way scientists think about how to combat the disease. “What we are learning is that, in order to develop better treatments for Alzheimer’s, not only do we need to attack the tip of the iceberg—that is, the beta-amyloid protein—but also all those other underlying mechanisms that are relevant to the aging process,” says Dr. Eliezer Masliah, director of the NIA’s Division of Neuroscience.

A Research Renaissance

As funding for Alzheimer’s research has increased, both at the federal level and through philanthropic programs such as Part the Cloud, promising new areas of research have flourished. Processes such as neuroinflammation and cellular senescence, scientists now believe, contribute to the disease—and they often start damaging the brain decades before the onset of Alzheimer’s symptoms.

Many of those treatments are already in the works. As of 2019, more than 500 new potential drug targets have been identified that address a variety of neurodegeneration areas. But according to Dr. Malú G. Tansey, the director of Center for Translational Research in Neurodegenerative Disease at the University of Florida College of Medicine, no single drug—and no single researcher—will provide a silver bullet. “The best approach is a team approach,” she says, “It’s going to take coordinated efforts across labs, departments, and institutions.”

As with cancer, diabetes, and other diseases, the future of Alzheimer’s treatment is likely to be personalized and multi-pronged. Already, science is steadily moving closer to that vision. An increase in the identification of biomarkers, which indicate the progression of the disease, is allowing doctors to better predict who might be at risk of developing Alzheimer’s. One day soon, Dr. Masliah hopes doctors will be able to design precision treatment strategies based on those biomarkers’ unique profiles. “For example, if somebody shows signs that they have inflammation in addition to a beta-amyloid or metabolic pattern, we’re going to combine drugs to attack all those areas,” he says.

The Future Is Personalized

The era of one-size-fits-all Alzheimer’s treatments is nearing an end. As with many other diseases, scientists expect, multi-pronged Alzheimer’s treatments will soon be tailor-made for individuals based on their unique genetic, biomarker, and lifestyle characteristics.

Developing all those drugs will take time—and a lot more scientific brain power. Luckily, the community of dementia scientists is expanding rapidly. The Alzheimer’s Association International Conference broke attendance records for the third consecutive year in 2019, and membership in the Association’s International Society to Advance Alzheimer’s Research and Treatment grew 10 percent in 2018. The Alzheimer’s Association wants to see those numbers continue to increase. “Over the past 15 years, largely because of limited Alzheimer’s funding, early career investigators went to other fields and made great discoveries,” Dr. Carrillo says. “That’s great for cancer, heart disease, HIV, and other diseases, but we want to attract them back into the Alzheimer’s field.”

At the University of Arizona, Dr. Brinton thinks it’s a better time than ever to join the fight against the disease. Research resources, she points out, will continue to surge. Part the Cloud, for one, plans to double the number of clinical trials it funds next year. In that environment, Dr. Brinton believes major breakthroughs are inevitable. “It is a phenomenally exciting time,” she says. “Those of us on the front lines of the battle are not looking back. We’re going forward and we’re confident.”