New Alzheimer’s drugs have eluded scientists

As another Alzheimer’s drug that targets plaque in the brain fails to improve cognition in patients, leading scientists say significant progress is being made in the search for effective treatments for the disease.

A new direction in Alzheimer’s research stems from evidence that several factors contribute to the development of the disease, not just beta-amyloid plaques, but other potential causes, including brain inflammation and diabetes-related conditions.

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

Amyloid plaques, clumps of protein in the brain that have long been considered a hallmark of Alzheimer’s, are still seen as a key player in the development of the disease, but a shift away from amyloid as the sole cause is the focus of the Alzheimer’s Association’s 2022 International Conference this week. In San Diego, top scientists are announcing the latest discoveries in the field, including new treatments for a disease that affects more than 6 million Americans.

The Alzheimer’s Association estimates that number will reach nearly 13 million by 2050.

On Tuesday, researchers at North Carolina-based T3D Therapeutics shared new Phase 2 trial data for an experimental non-amyloid drug called T3D-959 aimed at overcoming insulin resistance, which is common in Alzheimer’s patients.

According to John Didsbury, CEO of T3D Therapeutics, Alzheimer’s disease, often referred to as “type 3 diabetes,” is a brain-specific form of diabetes caused by a lack of glucose in the brain’s neurons. Low glucose levels in the brain may play a role in the decline in memory and thinking skills, he said.

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

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

Didsbury said the company doesn’t expect to start a phase 3 trial that will determine how well the treatment works for another year and a half, and the drug isn’t close to being sold to patients.

Still, the drug could 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 Edelmeier, senior director of research at the Alzheimer’s Association.

The amyloid hypothesis does not find a cure

Scientists have hoped that amyloid, which has been the focus of Alzheimer’s treatment research for the past three decades, will hold the key to solving Alzheimer’s. Plaque builds up around neurons—the cells responsible for sending and receiving signals from the brain—and eventually leads to memory and thinking problems in patients.

However, the recent controversy surrounding Biogen’s aducanumab, falsified studies and a series of failed clinical trials targeting amyloid have left some in the field demoralized.

More recently, pharmaceutical company Roche announced in June that its amyloid 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 participated in a phase 3 trial supported by the National Institute on Aging.

Donna Wilcock, assistant dean of biomedicine at the University of Kentucky, said the amyloid hypothesis “has gotten a lot of hits lately.” “Drug trials continue and are often unsuccessful.”

Experts expect to consider several mechanisms for diagnosis and treatment of the disease.

“It’s a comprehensive situation with research to try to figure out better ways to diagnose and treat,” Ramanan said.

Blood-based tests are also being developed that can more accurately predict the presence of beta-amyloid plaques in the brain, according to the Mayo Clinic’s Ramanan. This means patients no longer have to undergo expensive PET imaging scans or painful spinal taps, and it ensures they are enrolled in relevant clinical trials.

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

Can Exercise Prevent Alzheimer’s?

Because new pharmaceutical treatments have been available to patients for years, some Alzheimer’s researchers are increasingly looking 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 cognitive exercise, published at a conference on Tuesday, showed that exercise may halt cognitive decline in Alzheimer’s patients.

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

According to Edelmeier of the Alzheimer’s Association, exercise “may not only be a risk-reduction mechanism for developing dementia,” but “a healthy, balanced lifestyle can help reduce the risks.”

The main advantage of the exercise program is that doctors can immediately prescribe the drug to patients to reduce the risk of disease, rather than waiting years for clinical trials.

Does not reject amyloid

As outside research on amyloid accelerates, former Food and Drug Administration scientist Dr. Yaning Wang, CEO of a now clinical-stage biotech firm, urges scientists not to give up entirely on developing drugs to fight amyloid.

Similarly, Dennis Selkoe, a neuroscientist at Harvard Medical School and Brigham and Women’s Hospital, continues to develop drugs that target amyloid.

He co-authored a paper published last month in the journal PLOS Biology that found amyloid is still one of several factors that play a role in the development of the disease and noted that clinical trials targeting the plaque have been “plagued with missteps.”

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

Meanwhile, Selkoe calls for more research on tangled tau proteins, commonly found in Alzheimer’s patients, and activation of microglia, immune cells in the central nervous system that play a role in brain inflammation.

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

He says we should probably see more research discoveries showing the potential to slow down Alzheimer’s disease in the next year or two.

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