For Alzheimer’s researchers, a long and frustrating struggle to find a drug

A lot is riding on Biogen’s experimental drug. If approved, it “would be the first disease-modifying drug ever,” says George Vradenburg, chairman and co-founder of the advocacy group UsAgainstAlzheimer’s. The last time a drug was approved specifically for Alzheimer’s was 2003, and since then, the Alzheimer’s drug pipeline has spit out a bunch of duds.

More than 200 promising leads have fallen through just in the past decade. There has been an ongoing search for Alzheimer’s drugs since the 1990s, but “the long and short of it is that it’s not been successful,” says Lon Schneider, an Alzheimer’s researcher at the University of Southern California’s Keck School of Medicine.

These failures aren’t for lack of trying. Instead, they are evidence that the disease and its causes are much more complex than researchers first appreciated. “We were blind to this [complexity]. Things looked simpler than they really are,” says Richard Hodes, director of the National Institute on Aging (NIA).

Dementia, confusion and personality changes are hallmark symptoms of Alzheimer’s, but the disease can be definitively diagnosed only by examining the brain in an autopsy. The brains of people with Alzheimer’s show a loss of nerve cells and the connections between them along with signature plaques and tangles of proteins called beta amyloid and tau.

Until relatively recently, the search for a drug largely centered around the idea that Alzheimer’s develops and progresses in a specific pattern. Toxic plaques of beta amyloid clump together between neurons in the brain. As these accumulate, they’re accompanied by a buildup of tangled masses of tau inside neurons. These changes are accompanied by inflammation and cell death in the brain. Many drug candidates have aimed to clear or disarm beta amyloid, under the logic that eliminating amyloid plaques would halt or reverse the process and thus Alzheimer’s itself.

Biogen’s drug is just one of many designed to clear beta amyloid, and so when its trials were halted last spring, it initially seemed like another repudiation of the “amyloid hypothesis.”

But interest was reignited when Biogen announced in October that it had reanalyzed the data from the two halted clinical trials of aducanumab and found that patients receiving the highest doses of the drug seemed to experience less cognitive decline than the placebo group in one of the trials. If aducanumab really works, it would be a triumph for the amyloid approach.

“The Biogen results are the most exciting results we’ve seen in a while,” says Howard Fillit, executive director and chief science officer at the Alzheimer’s Drug Discovery Foundation.

Others in the field remain skeptical, however.

The benefits were found in only one of the two trials, and the company’s analysis broke “all the rules, really, about how you analyze data and report it,” University College London Alzheimer’s researcher Robert Howard told the journal Science.

In a commentary published in the Lancet Neurology, Schneider argues that Biogen’s methods for parsing the trial data means that “treatment effects are likely exaggerated.”

The search for Alzheimer’s treatments is riddled with failed amyloid drugs, and amyloid has begun to look like an imperfect target. For one thing, about 40 percent of people in their 70s have amyloid plaques but no dementia, Schneider says. At the same time, some people with dementia have not developed amyloid plaques.

Rather than being a driver of Alzheimer’s disease process, amyloid may represent its aftermath.

“Amyloid plaques might actually be signs of the brain doing its job when it’s subject to injury or inflammation,” Schneider says. And if that is the case, it would mean that attempts to treat Alzheimer’s disease by cleaning up amyloid are futile.

“I compare amyloid plaques to tombstones,” Schneider says. You can go into a cemetery and remove tombstones, but it will not make the people buried there any less dead.

The amyloid hypothesis dominated the search for an Alzheimer’s drug for a long time, but a different way of thinking about Alzheimer’s is coming to the forefront, Vradenburg says. The new approach says that the reason the approaches we’ve been using to look for Alzheimer’s drugs have failed is that there is not one single way that the disease develops and progresses. Instead, it now appears as if there may be many different contributors and pathways to the disease. And in that case, Vradenburg says, we need to treat the disease in a more individualized way.

Instead of having a single drug for Alzheimer’s, we might need multiple treatments that target each of the different ways that it can develop and manifest. The drug pipeline has become more diversified, with clinical trials looking at other targets such as inflammation, the immune system and metabolic processes that might be involved in Alzheimer’s, says Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association.

The expectation that we will find an across-the-board drug appears to be fading.

“We’re peeling back the onion — asking, ‘How can we be thinking of combination therapies?’ ” Snyder says.

In 2014, drugs targeting amyloid beta made up the largest share of NIA-funded projects. But by 2018, inflammation had taken over as the most common target of experimental drug therapies. Inflammation is a hallmark of aging, and it also appears to play a role in Alzheimer’s.

Funding for the disease has increased dramatically in the past decade. The NIA’s support climbed more than fourfold between 2013 and 2019. In 2020, federal funding for Alzheimer’s research rose to $2.8 billion. This influx of money is helping to recruit new scientists into the field, Hodes says, noting that the field has undergone a “change in direction” toward more collaboration and data sharing.

While the research hasn’t produced a drug yet, it has advanced understanding of the disease in important ways that may yet lead to effective treatments.

For now, some of the most promising approaches to addressing Alzheimer’s are non-pharmaceutical. The NIA is sponsoring 86 studies of nondrug interventions that may help, including exercise, diet, cognitive training and sleep. The U.S. Pointer study is a two-year clinical trial examining whether lifestyle interventions can protect older adults from cognitive impairment and dementia.

Snyder says the study builds on a similar one conducted in Finland and published in 2015, which found that a program of physical activity, cognitive simulation, a Mediterranean diet and controlling heart disease risk factors offered some protection against cognitive decline. Participants were at risk for dementia, but none had it. After two years, the risk of exhibiting cognitive decline was 30 percent higher in the control group than in the one assigned to the lifestyle interventions.

Everyone wants a cure, but for now we may have to settle for the benefits that come from the healthy habits we already know we should adopt.

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