As new Alzheimer’s drugs keep failing, scientists are shifting focus

As new Alzheimer’s drugs keep failing, scientists are shifting focus

As another Alzheimer’s drug that targets plaque buildup in the brain fails to improve cognition in patients, leading scientists say a significant shift is underway in the quest for effective treatments for the disease.

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

“It doesn’t appear that there is 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 thought to be a hallmark of Alzheimer’s, are still considered a key factor in the development of the disease, but moving away from amyloid as the sole cause is a focus at this week’s 2022 Alzheimer’s Association International Conference in San Diego , where top scientists publish the latest discoveries in the field, including potential new treatments for the disease, which affects more than 6 million Americans.

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

On Tuesday, researchers at North Carolina-based T3D Therapeutics announced new Phase 2 study data for an investigational non-amyloid drug called T3D-959, which aims to overcome insulin resistance commonly seen in Alzheimer’s patients.

Alzheimer’s disease is often referred to as “type 3 diabetes,” a brain-specific form of diabetes that’s the result of a lack of glucose in the brain’s neurons, said John Didsbury, CEO of T3D Therapeutics. The reduced glucose in the brain could play a role in reducing memory and the ability to think, he said.

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

Study 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 a Phase 3 trial – which would determine how well the treatment works – to start in the next year and a half, and the drug is nowhere near being marketed to patients .

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

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

The amyloid hypothesis finds no treatments

Scientists had hoped that amyloid — which has been the focus of Alzheimer’s treatment research for the past three decades — would hold the key to solving Alzheimer’s. The plaque forms around neurons – the cells responsible for sending and receiving signals from the brain – eventually leading to impaired memory and thinking in patients.

However, the recent controversy surrounding Biogen’s aducanumab, claims of fake research, and a string of failed clinical trials over the years targeting amyloid have demoralized some in the field.

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. About 250 people took part in the phase 3 study, which was supported by the National Institute on Aging.

The amyloid hypothesis “has suffered a lot of setbacks lately,” said Donna Wilcock, associate dean of biomedicine at the University of Kentucky. “The drug trials keep coming through and mostly failing.”

Experts believe that diagnosis and treatment of the disease may need to consider multiple mechanisms.

“It’s kind of an all-man-on-deck situation with research to try to identify better diagnostic and treatment options,” Ramanan said.

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

“These blood markers are currently being used extensively in research studies, and there is some optimism that they will see more clinical use in the coming years,” Ramanan said.

Can exercise prevent Alzheimer’s?

Because it can take years for new pharmaceutical treatments to become available to patients, some Alzheimer’s researchers are looking more at early detection and prevention, such as: B. Exercise to slow the onset or progression of the disease.

Data from the longest-ever Phase 3 study of cognition exercise, released at Tuesday’s conference, found exercise can halt cognitive decline in Alzheimer’s patients.

Three hundred patients in the study – from the Alzheimer’s Disease Cooperative Study in collaboration with Wake Forest and the YMCA – were randomly assigned to undergo 18 months of moderate-intensity aerobic exercise or stretching, balance and range-of-motion exercise. Neither group showed 12-month declines on cognitive tests.

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

A key benefit of an exercise program is that doctors can prescribe it to patients right away to reduce their risk of disease, without having to wait years for drug clinical trials.

Don’t give up amyloid

As research accelerates outside of amyloid, former Food and Drug Administration scientist Dr. Yaning Wang, now CEO of a clinical-stage biotech company, is urging scientists not to abandon amyloid drug development altogether.

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

He co-authored a paper published last month in the journal PLOS Biology, noting that amyloid is still likely one of several factors involved in the development of the disease and that clinical trials target the plaque , “full of missteps” were.

Both Wang and Selkoe said scientists are eagerly awaiting data from another amyloid-targeted drug from Biogen and Eisai, which is expected in the fall.

At the same time, Selkoe calls for more research on treatments that target tangled tau proteins, which are also common in Alzheimer’s patients, and on activating microglia, the central nervous system immune cells involved in brain inflammation.

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

He said it’s only a matter of time before we see more research discoveries showing the potential for slowing Alzheimer’s disease, possibly within the next year or two.

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