As new Alzheimer’s drugs continue to fail, scientists are changing their focus

As yet another Alzheimer’s drug that targets plaque buildup in the brain fails to improve patients’ cognitive function, top scientists say a major shift is underway in the search for effective treatments for the disease.

The new direction in Alzheimer’s research — away from focusing solely on beta-amyloid plaques to other possible causes, including brain inflammation and conditions related to diabetes — comes from growing evidence that many factors contribute to the development of the disease .

“There doesn’t seem to be a single superstar mechanism that is the magic solution,” said Dr. Vijay Ramanan, a neurologist at the Mayo Clinic in Rochester, Minnesota.

Amyloid plaques, clumps of protein in the brain long considered a hallmark of Alzheimer’s disease, are still thought to be a key factor in how the disease develops, but the shift away from amyloid as the sole cause is a focal point of the International Congress of Alzheimer’s Association 2022. in San Diego, where leading scientists publish the latest discoveries in the field, including potential new treatments for the disease, which affects more than 6 million Americans.

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

On Tuesday, researchers at North Carolina-based T3D Therapeutics shared new phase 2 trial data for an experimental non-amyloid drug, called T3D-959, that aims to overcome the insulin resistance often seen in Alzheimer’s patients.

Alzheimer’s disease is often referred to as “Type 3 Diabetes,” a brain-specific form of diabetes that is the result of a lack of glucose in the brain’s neurons, said John Didsbury, CEO of T3D Therapeutics. Reduced glucose in the brain may play a role in impaired memory and reasoning skills, he said.

T3D-959, he said, tries to overcome this “brain starvation.”

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

Didsbury said the company doesn’t expect to start a phase 3 trial — which would determine how well the treatment works — for another year and a half, and the drug is nowhere close to being on the market for patients.

Still, the drug may be a “ray of hope” for Alzheimer’s patients, Didsbury said, noting the unmet need for treatments that target other aspects of the disease besides amyloid.

“It’s really an incredibly exciting time right now,” said Rebecca Edelmayer, senior director of scientific engagement at the Alzheimer’s Association.

The amyloid hypothesis fails to find cures

Scientists hoped that amyloid – which has been the main focus of Alzheimer’s treatment research for the past three decades – would be the key to solving Alzheimer’s. Plaque builds up around neurons – the cells responsible for sending and receiving signals from the brain – which eventually leads to impaired memory and thinking in patients.

However, recent controversy surrounding Biogen’s aducanumab, allegations of falsified research and a string of failed clinical trials over the years targeting amyloid have left some in the field discouraged.

Most recently, pharmaceutical company Roche announced in June that its amyloid-targeting 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, which was sponsored by the National Institute on Aging, involved about 250 people.

The amyloid hypothesis “has been taking a lot of hits lately,” said Donna Wilcock, assistant dean of biomedicine at the University of Kentucky. “Drug trials keep going and mostly fail.”

Experts expect that diagnosis and treatment of the disease may need to take into account multiple mechanisms.

“It’s a general situation with research to try to identify better diagnostic and treatment options,” Ramanan said.

Also, blood-based tests are under way that can accurately predict the presence of beta-amyloid plaques in the brain, said the Mayo Clinic’s Ramanan. This would mean that patients would no longer need to have expensive PET scans or painful spinal taps and would ensure that they would be enrolled in appropriate clinical trials.

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

Can exercise prevent Alzheimer’s?

Since new drug treatments may be years away from being available to patients, some Alzheimer’s researchers are looking more to early detection and prevention, such as exercise, to slow the onset or progression of the disease.

Data from the longest-running phase 3 trial of exercise on cognitive function published at the conference on Tuesday found that exercise can halt cognitive decline in Alzheimer’s patients.

Three hundred patients in the trial — from the Alzheimer’s Disease Collaborative Study in partnership with Wake Forest and the YMCA — were randomized to moderate-intensity aerobic exercise or stretching, balance and range of motion for 18 months. Neither group showed 12-month declines in cognitive tests.

The data suggest that exercise “may be a potential risk-reducing mechanism not only for developing dementia” but “a whole, healthy, balanced lifestyle approach to reducing risk,” said Edelmayer, of the Alzheimer’s Association.

A key advantage of an exercise program is that doctors could prescribe it to patients immediately to reduce their risk of disease, without waiting years for clinical drug trials.

We are not giving up amyloid

While research outside of amyloid is accelerating, former Food and Drug Administration scientist Dr. Yaning Wang, now CEO of a clinical-stage biotech company, is urging scientists not to give up entirely on developing drugs that fight amyloid.

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

He authored a paper published in the journal PLOS Biology last month, which noted that amyloid is still likely one of many factors that play a role in the development of the disease and that clinical trials targeting the plaque have been “riddled with errors.” .

Both Wang and Selkoe said scientists are looking forward to data from another amyloid-targeting drug, from Biogen and Eisai, expected in the fall.

At the same time, Selkoe is calling for more research into treatments that target tangled tau proteins, also commonly found in Alzheimer’s patients, and the activation of microglia, the immune cells of the central nervous system that play a role in brain inflammation.

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

He said it’s only a matter of time before we see more research breakthroughs that show potential for slowing Alzheimer’s disease, possibly within a year or two.

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