As yet another Alzheimer’s drug that targets plaque buildup in the brain fails to improve cognition in patients, leading scientists have 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 diabetes-related conditions – stems 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, lumps of protein in the brain long considered a hallmark of Alzheimer’s, are still seen as a key player in the development of the disease, but the shift from amyloid as the sole cause is a focus of the international conference of Alzheimer’s. Alzheimer’s Association of 2022 this week in San Diego, where top scientists are publishing the latest findings in the field, including potential new treatments for the disease, which affects more than 6 million Americans.
According to an estimate from the Alzheimer’s Association, by 2050, that number is expected to rise to nearly 13 million.
On Tuesday, researchers at North Carolina-based T3D Therapeutics shared new data from the Phase 2 trial for a non-amyloid investigational drug, called T3D-959, which aims to overcome insulin resistance often seen in patients. Alzheimer’s.
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 in glucose, said John Didsbury, CEO of T3D Therapeutics. Decreased brain glucose may play a role in decreased memory and reasoning skills, he said.
T3D-959, he said, tries to overcome this “brain hunger”.
The results of the studies 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 has no plans 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 near commercialization for patients.
However, the drug could be a “ray of hope” for Alzheimer’s patients, Didsbury said, stressing 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 science engagement at the Alzheimer’s Association.
The amyloid hypothesis fails to find treatments
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 resolving Alzheimer’s. Plaque builds up around neurons, the cells responsible for sending and receiving signals from the brain, ultimately leading to impaired memory and thinking in patients.
However, Biogen’s recent aducanumab controversy, falsified research allegations, and a string of failed clinical trials over the years against amyloid have demoralized some in the field.
More recently, pharmaceutical company Roche announced in June that its amyloid-targeted drug, crenezumab, has failed to slow or prevent cognitive decline in people with a rare genetic mutation that causes early-onset Alzheimer’s. . The Phase 3 study, supported by the National Aging Institute, enrolled around 250 people.
The amyloid hypothesis “has taken a lot of hits lately,” said Donna Wilcock, assistant dean of biomedicine at the University of Kentucky. “Drug trials keep coming and, for the most part, fail.”
Experts expect the diagnosis and treatment of the disease to consider multiple mechanisms.
“It’s a well-rounded type of situation with research to try and identify better diagnosis and treatment options,” Ramanan said.
Blood tests that can accurately predict the presence of beta-amyloid plaques in the brain are also being developed, said Ramanan of the Mayo Clinic. This would mean that patients would no longer need to undergo costly PET imaging scans or painful spinal taps and would ensure they are enrolled in appropriate clinical trials.
“Now these blood markers are being used extensively in research studies and there is a good deal of optimism that they will be used more widely in the clinic in the coming years,” said Ramanan.
Can Exercise Prevent Alzheimer’s?
As new pharmaceutical treatments may take years before patients are available, some Alzheimer’s researchers are looking more at early detection and prevention, such as exercise, to slow the onset or progression of the disease.
Data from the longest Phase 3 study on exercise on cognition released Tuesday at the conference found that 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 YMCA – were randomized to moderate-intensity aerobic training or stretching, balance, and freedom of movement for 18 months. Neither group showed 12-month drops in cognitive tests.
The data suggests that exercise “could be a mechanism to potentially reduce risk not only for developing dementia” but “an overall healthy and balanced approach to risk reduction,” said Edelmayer, of the Alzheimer’s Association.
A key benefit of an exercise program is that doctors can immediately prescribe it to patients to reduce the risk of contracting the disease, without waiting years for clinical drug trials.
Don’t give up on amyloid
As research outside of amyloid accelerates, former Food and Drug Administration scientist Dr. Yaning Wang, now CEO of a clinical-stage biotech company, is urging scientists not to completely abandon development of 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 co-authored an article published in the journal PLOS Biology last month which noted that amyloid is still likely one of several factors that play a role in the development of the disease and that clinical trials on plaque have been “full of steps. false “.
Both Wang and Selkoe said scientists are eagerly awaiting data on another amyloid-targeted drug, from Biogen and Eisai, expected in the fall.
At the same time, Selkoe calls for further research on treatments that target entangled tau proteins, which are also commonly found in Alzheimer’s patients, and 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 the accumulation of amyloid,” he said.
He said it’s only a matter of time before we see further research findings showing the potential to slow Alzheimer’s disease, perhaps within a year or two.
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