Scientists shift focus as new Alzheimer’s drugs continue to fail

A major shift is underway in the search for an effective treatment for the disease, as yet another Alzheimer’s drug that targets plaque buildup in the brain fails to improve patients’ cognition. said.

A new direction in Alzheimer’s research — away from focusing solely on beta-amyloid plaques, to focus on other potential causes including: brain inflammation and diabetes-related conditions — coming from growing evidence that multiple factors contribute to the development of the disease.

Dr. Vijay Ramanan, a neurologist at the Mayo Clinic in Rochester, Minnesota, said:

Amyloid plaques, clumps of protein in the brain that have long been thought to be a hallmark of Alzheimer’s disease, are still thought to play a key role in the development of the disease, but amyloid as the sole causative The transformation of is this week’s focus. 2022 Alzheimer’s Association International Conference In San Diego, leading scientists present their latest discoveries in the field. Over 6 million Americans.

By 2050, that number is expected to rise to nearly 13 million, according to Alzheimer’s Association estimates.

On Tuesday, researchers at T3D Therapeutics, based in North Carolina, announced a new phase II trial of an non-amyloid drug called T3D-959, aimed at overcoming insulin resistance common in Alzheimer’s patients. shared the data.

Alzheimer’s disease, often called “type 3 diabetes,” is a brain-specific form of diabetes that occurs because nerve cells in the brain lack glucose, said John Didsbury, CEO of T3D Therapeutics. increase. A decrease in glucose in the brain may be involved in a decline in memory and reasoning ability, he said.

T3D-959 is trying to overcome this “brain hunger,” he said.

Trial results presented at the conference showed that the drug, which targets two different nuclear receptors in the brain responsible for energy production, appears safe and well tolerated.

Didsbury said the company has no plans to start a Phase 3 trial for another year and a half.

Still, the drug could be a “beacon of hope” for Alzheimer’s patients, Didsbury said, pointing to an unmet need for treatments that target other aspects of the disease besides amyloid. It pointed out.

“It’s actually an incredibly exciting time,” said Rebecca Edelmeyer, senior director of scientific engagement at the Alzheimer’s Association.

Amyloid hypothesis fails to find cure

Scientists hoped that amyloid, which has been a major focus of Alzheimer’s disease treatment research for the past 30 years, could be the key to solving Alzheimer’s disease. Plaques build up around neurons (cells that send and receive signals from the brain) and eventually lead to impaired memory and thinking.

However Recent controversy over Biogen’s aducanumab, Falsified Research Allegations And a long string of failed clinical trials targeting amyloid has left some researchers demoralized.

Recently, Pharmaceutical company Roche announced In June, the company’s amyloid-targeted drug crenezumab failed to slow or prevent cognitive decline in people with a rare genetic mutation that causes early-onset Alzheimer’s disease. The Phase 3 trial enrolled approximately 250 people.

Donna Wilcock, associate dean of biomedicine at the University of Kentucky, said the amyloid hypothesis “has had a lot of hits lately”. has ended.”

Experts anticipate that multiple mechanisms will need to be considered in diagnosing and treating the disease.

“This is an all-encompassing situation with research that seeks to identify better diagnostic and treatment options,” Ramanan said.

A blood-based test is also in development that can accurately predict the presence of beta-amyloid plaques in the brain, said Ramanan of the Mayo Clinic. It means that you no longer need to take a course and you are guaranteed to be enrolled in the appropriate clinical trial.

“These blood markers are now being widely deployed in research studies, and there is considerable optimism that they will be more widely deployed in clinics in the next few years,” said Ramanan.

Can exercise prevent Alzheimer’s disease?

Because it can be years before new pharmaceutical treatments are available to patients, some Alzheimer’s researchers are focusing more on early detection and prevention, such as exercise, which slows the onset and progression of the disease. I’m looking.

Data from the longest-ever phase 3 trial of exercise on cognition, presented at a conference on Tuesday, found that exercise could slow cognitive decline in people with Alzheimer’s disease.

The Alzheimer’s Disease Collaborative Study, in partnership with Wake Forest and the YMCA, randomized 300 patients in the trial to 18 or 18 moderate-intensity aerobic training or stretching, balance, and range-of-motion training. took place for a month. Neither group showed him a 12-month decline in cognitive tests.

The Alzheimer’s Association’s Edelmeyer said that exercise “could be a mechanism to reduce the risk of developing dementia,” but also that “an overall healthy and balanced diet to reduce risk.” suggesting that it is a lifestyle approach.

A major advantage of exercise programs is that doctors can quickly prescribe them to patients to reduce their risk of disease, rather than waiting years for clinical trials.

don’t give up on amyloid

While non-amyloid research accelerates, Yaning Wang, Ph.D., a former Food and Drug Administration scientist and now CEO of a clinical-stage biotech company, won’t abandon development of amyloid-fighting drugs altogether. I urge scientists to

Similarly, Denise Selcoe, a neurologist at Harvard Medical School and Brigham and Women’s Hospital, is pushing the continued development of drugs that target amyloid.

he co-authored a published paper In the journal PLOS Biology Last month, he noted that amyloid is still likely to be one of several factors involved in the development of the disease, and that clinical trials targeting plaque were “riddled with failures.”

Both Wang and Selkoe said scientists are eagerly awaiting data from another amyloid-targeting drug. From Biogen and Eisaiis expected in the fall.

At the same time, Selkoe calls for further research into therapies that target the tangled tau protein, which is also common in Alzheimer’s patients, and the activation of microglia, central nervous system immune cells involved in brain inflammation. .

Tau and microglia “seem to be important additional factors, but they appear to be caused by amyloid accumulation,” he said.

He says it’s only a matter of time, perhaps in the next year or two, before more research shows it can slow the progression of Alzheimer’s disease.

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