Will We Ever Find a Cure for Dementia?

Diversifying the drug pipeline

Scientists all over the world are following a similar path. They’re looking beyond the single strategy most dementia researchers have studied in the past — clearing toxic amyloid plaques from the brain, a hallmark of Alzheimer’s disease — and instead are pumping more possibilities than ever before into dementia’s drug pipeline.

The roles the immune system and the metabolic system play in the development of dementia are under the microscope. Researchers — including many funded by the National Institutes of Health (NIH), which is expected to spend $2.8 billion on Alzheimer’s research in 2020 — are also studying everything from blood vessels to hormonal factors to solve the dementia dilemma.

“We now know that the brain is part of a larger system,” explains Rebecca Edelmayer, director of scientific engagement at the Alzheimer’s Association. “And there may be many other ways to target the overall health of the brain” so that it stays as fit as possible throughout the aging process and is able to “stave off signs and symptoms of Alzheimer’s disease and other dementias,” she adds.

Some of the most promising drug candidates in the packed pipeline of possibilities help to preserve and strengthen the communication channels between nerve cells, explains Suzana Petanceska, a program director in the Division of Neuroscience at the NIH’s National Institute on Aging, which is currently supporting more than 230 dementia-focused clinical trials – including more than 40 drug trials – and recently established two new research centers dedicated to diversifying the Alzheimer’s disease drug development pipeline. 

With dementia, these channels become damaged or disrupted, leading to memory loss and a cascade of debilitating effects. One theory currently being tested in clinical trials is that if we prevent the death of these neurons, or find a way to stimulate the birth of new ones, then the brain becomes more resilient when faced with disease.

“We all have resilience, but when we talk about how we protect the brain, some of the ways to do that is actually to harness the brain’s natural repair mechanisms and activate them so that it can recover in the face of injury,” Petanceska says.

The tricky part is figuring out the best time to target these processes. The symptoms of Alzheimer’s and other dementias typically set in later in life, but “the disease process begins many, many years before,” Petanceska explains. So having a “reliable, noninvasive” way to track warning signs of the disease before the damage is done will be key to delivering effective treatments.

The DDF’s portfolio also includes companies and projects that are investigating ways to protect the health of brain cells to treat Alzheimer’s disease and other neurodegenerative disorders. AstronauTx, for example, which received DDF funding in 2019, is focused on developing drugs to modify malfunctioning astrocytes, a type of brain cell that supports the neurons and their communication channels.

Advancements in amyloid and tau

All that’s not to say the treatment theories that held so much promise in the ’90s and early 2000s have been totally abandoned, despite decades of failed clinical trials. Much of the research in the field continues to focus on amyloid, as well as tau — another hallmark protein of Alzheimer’s disease that forms tangles inside the neurons.

This year, all eyes are on aducanumab, an anti-amyloid drug that is headed to the Food and Drug Administration (FDA) for review. It was shown in clinical trials to reduce the amount of amyloid in the brains of people with early Alzheimer’s disease. U.S. drugmaker Biogen reports that participants who received high doses of the antibody saw improvements in memory and thinking skills, and were better able to perform activities of daily living, such as laundry and personal finances. If approved, aducanumab will be the first drug available to treat people with Alzheimer’s disease. Currently, the handful of dementia drugs available help only to alleviate symptoms.

Christopher H. van Dyck, M.D., professor of psychiatry, neurology and neuroscience and director of the Alzheimer’s Disease Research Unit at the Yale School of Medicine, points to two other amyloid-clearing therapies that are far along in the clinical trial process — BAN2401 (from companies Biogen and Eisai) and gantenerumab (from Roche). If aducanumab doesn’t clear FDA review, “you’d bet on one of these” becoming the first available treatment for Alzheimer’s disease, he says.

Timing is one thing that sets the more successful and the promising anti-amyloid therapies apart from their failed predecessors. Until recently, every trial that aimed to stop or slow the progression of dementia failed. “And it failed because we were giving these drugs to people who have symptoms” of the disease, explains Michael Rafii, M.D., an associate professor of clinical neurology at the Keck School of Medicine of the University of Southern California, and medical director of the Alzheimer’s Therapeutic Research Institute.

And giving drugs to people who are symptomatic “is just too late,” he says. Somebody who has dementia already has widespread damage to the brain. “And unfortunately, when there’s any damage to the brain, it’s permanent. You can’t go back. So early treatment is the key,” he adds.

To Rafii’s point, trials targeting people in the earlier stages of their disease have seen success. One new trial is even testing to see whether removing amyloid in people who have no Alzheimer’s symptoms will provide a preventative benefit. “So that’s a very exciting study,” Rafii adds.

Targeting the tau tangles is another big area of focus in the field. Unlike amyloid plaques, which can be present in the brains of people who are asymptomatic, tau tangles are more closely correlated with clinical symptoms of the disease. Plus, their presence is seen in a number of neurodegenerative disorders, not just Alzheimer’s.

“If we are able to find a therapeutic that is helpful for really staving off the changes that occur with tau, we may actually be able to find therapeutics that are beneficial to multiple dementias,” the Alzheimer’s Association’s Edelmayer says.

'Cure' could take many forms

As varied as the research pipeline is, most experts agree on one thing: When it comes to finding a way to stop, slow or prevent dementia, it won’t boil down to one drug treatment or even one drug target. Rather, it will be a combination approach, perhaps involving drugs that clear the amyloid plaques, knock out the tau tangles, target problem proteins and improve the synaptic health of the nerve cells in the brain.

Patients may also receive nonpharmacological prescriptions from their doctors. Some of the most recent research has shown that cardiovascular health and cerebral vascular health play a critical role in overall brain health throughout one’s lifetime. Exercise, diet and sleep have all been shown to reduce risk of cognitive decline in adults. What’s more, a landmark study in 2018 showed that intensive blood pressure control significantly lowered the chances that participants developed mild cognitive impairment.

The mishmash of therapies likely won’t cure dementia, but as Rafii explains, “we have very few cures in medicine.” He and others in the field, including the DDF’s Grant, are optimistic, however, that the ongoing advancements will lead to treatments that can delay the disease and improve the lives of millions.

“What I’m seeing is great progress in the building blocks, the foundation of new future therapeutic approaches,” Grant says.