As new Alzheimer’s drugs continue to fail, researchers are shifting their focus

As yet another Alzheimer’s drug targeting plaque buildup in the brain fails to improve cognition in patients, leading researchers 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.

“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, are still seen as a key player in how the disease progresses, but the shift away from amyloid as the sole cause is a focal point at this week’s 2022 Alzheimer’s Association International Conference in San Diego, where top researchers releases the latest findings 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 by the Alzheimer’s Association.

On Tuesday, researchers at North Carolina-based T3D Therapeutics shared new Phase 2 study data for an experimental non-amyloid drug, called T3D-959, which 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 results from the brain’s neurons lacking glucose, said John Didsbury, CEO of T3D Therapeutics. The reduced glucose in the brain may play a role in reduced memory and reasoning skills, he said.

T3D-959, he said, appears 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 – appears to be safe and well tolerated.

Didsbury said the company doesn’t expect to start a Phase 3 trial — which will determine how well the treatment works — for another 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, 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 of science engagement at the Alzheimer’s Association.

The amyloid hypothesis fails to find treatments

Scientists had 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. The 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, the 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 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 study, which the National Institute on Aging supported, enrolled about 250 people.

The amyloid hypothesis has “taken a lot of hits lately,” said Donna Wilcock, assistant dean of biomedicine at the University of Kentucky. “The drug trials keep coming through and mostly fail.”

Experts expect that diagnosis and treatment of the disease must consider several 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 under development are blood-based tests that can accurately predict the presence of beta-amyloid plaques in the brain, Mayo Clinic’s Ramanan said. It will mean that patients no longer need to have expensive PET imaging scans or painful spinal taps, and it will ensure that they are enrolled in appropriate clinical trials.

“These blood markers are being widely deployed in research studies now, and there is a good deal of optimism that in the coming years they will become more widespread in the clinic,” Ramanan said.

Can exercise prevent Alzheimer’s?

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

Data from the longest phase 3 study of exercise on cognition released at the conference on Tuesday found that exercise can halt cognitive decline in Alzheimer’s patients.

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

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

An important advantage of an exercise program is that doctors can prescribe it to patients right away to reduce the risk of the disease, without waiting years for clinical drug trials.

Does not give up amyloid

As research beyond amyloid accelerates, former Food and Drug Administration researcher Dr. Yaning Wang, now CEO of a clinical-stage biotech firm, is urging researchers not to completely abandon development of amyloid-fighting drugs.

Similarly, Dennis Selkoe, a neurologist at Harvard Medical School and Brigham and Women’s Hospital, is 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 to be one of several factors that play a role in the development of the disease, and that clinical trials targeting plaques have been “fraught with missteps.”

Both Wang and Selkoe said researchers 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, which are also often found in Alzheimer’s patients, and activation of microglia, the 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 precipitated by amyloid accumulation,” he said.

He said it’s only a matter of time before we see more research findings showing potential to slow Alzheimer’s disease, possibly in the next year or two.

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