As new Alzheimer’s drugs have failed, scientists are shifting focus to other potential causes

As yet another Alzheimer's drug targeting plaque buildup in the brain fails to improve cognition in patients, leading scientists said a significant 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 potential causes, including brain inflammation and conditions related to diabetes — comes from growing evidence that multiple factors contribute to the development of the disease.

“It doesn’t seem that there’s one 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, are still seen as a key player in how the disease develops, but the turn from amyloid as a sole cause is a focal point of this week’s 2022 Alzheimer’s Association International Conference in San Diego, where top scientists are releasing 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, according to an estimate from the Alzheimer’s Association.

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 the brain’s neurons lacking glucose, said John Didsbury, the CEO of T3D Therapeutics. The decreased glucose in the brain may play a role in decreased memory and reasoning skills, he said.

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

Trial results presented at the conference showed 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 begin 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 marketed to 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 actually an incredibly exciting time right now,” said Rebecca Edelmayer, senior director for scientific engagement at the Alzheimer’s Association.

Amyloid hypothesis fails to find treatments

Scientists had been hopeful that amyloid — which has been the primary focus of Alzheimer’s treatment research for the past three decades — would be the key to solving Alzheimer’s. The plaque builds up 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 around Biogen’s aducanumab, allegations of falsified research and a series of failed clinical trials over the years targeting amyloid have left some in the field demoralized.

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 the National Institute on Aging supported, enrolled around 250 people.

The amyloid hypothesis has “been taking a lot of hits lately,” said Donna Wilcock, the assistant dean of biomedicine at the University of Kentucky. “The drug trials keep coming through and for the most part, failing.”

Experts expect diagnosis and treatment of the disease may have to consider multiple mechanisms.

"It’s an all-hands-on-deck kind of situation with research to try to identify better diagnosis and treatment options," Ramanan said.

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

“These blood markers are being deployed widely in research studies now and there’s a fair amount of optimism that in the coming years, they will be more widely deployed in the clinic,” Ramanan said.

Can exercise prevent Alzheimer's?

Since new pharmaceutical treatments may be years from being available for 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-ever phase 3 trial of exercise on cognition released at the conference on Tuesday found that exercise may stall cognitive decline in Alzheimer’s patients.

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

The data suggest exercise "may be a mechanism of potentially reducing risk for not only 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 could prescribe it to patients right away to reduce their risk of the disease, without waiting years for clinical drug trials.

Not giving up on amyloid

While research outside amyloid is accelerating, former Food and Drug Administration scientist, Dr. Yaning Wang, now the CEO of a clinical-stage biotech firm, is urging scientists to not wholly abandon the development of amyloid-fighting drugs.

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

Both Wang and Selkoe said scientists are eagerly awaiting 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 they appear to be precipitated by amyloid accumulation,” he said.

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

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