In Trials: A Powerful Magnet for Zapping Alzheimer’s Away

Treatment with a powerful magnet is one of the newest experimental therapies being used to try to turn back the clock on Alzheimer’s disease. The scientific name is repetitive transcranial magnetic stimulation (rTMS) — and it’s already been approved in the U.S. to treat drug-resistant depression, OCD, migraines, and cravings for smoking. Now, it’s in trials for Alzheimer’s.

rTMS is a non-invasive form of brain stimulation: Unlike other brain-zapping therapies, like deep brain stimulation, rTMS doesn’t require surgery. Instead, it uses a magnetic coil to zap specific parts of the brain to help reset dysfunctional patterns of brain activity. 

Sinaptica Therapeutics ran a recent 24-week Phase 2 trial of a personalized rTMS treatment to understand its potential for Alzheimer’s treatment — and the company reports that they found it was able to stop disease progression in people with mild to moderate Alzheimer’s. The next step: to see whether these results hold, and whether the treatment is safe, in a next phase of trials.

How might rTMS work for Alzheimer’s?

In the past 10 years, scientists have been experimenting with rTMS for Alzheimer’s. Across many small studies, there is evidence that zapping the right part of the brain could help treat the disease. But it’s been a bumpy road: In the 2010s, biotech company Neuronix Ltd. tested out an rTMS device called NeuroAD, but clinical trials failed and the device was rejected by the FDA in 2018. Neuronix closed its doors a year later. But Sinaptica’s version of rTMS works differently than NeuroAD: It uses a different zapping protocol that targets a different brain region and personalizes the brain-zapping dose to each person.

Sinaptica targets the precuneus, a brain region that plays an important role in the default mode network, a collection of brain regions that regularly communicate with each other to coordinate thinking and memory. In Alzheimer’s disease, beta-amyloid plaque builds up in the parts of the brain like the precuneus. 

“We see very clear evidence that the nodes of the network are starting to disconnect, and that is highly correlated with Alzheimer’s progression,” Ken Mariash, CEO of Sinaptica Therapeutics, told Being Patient.

Zapping the brain in the right part of the precuneus activates a process called neuroplasticity, which allows brain cells to form new connections and strengthen existing ones. 

To zap the right part of the brain, the researchers use EEG, a non-invasive technique that detects the brain’s electrical signals, to calibrate the device. Before treatment, each participant goes through a 45-minute calibration where EEG is used alongside rTMS to find the best spot and optimal dose for treatment. 

“It’s like active sonar,” said Mariash. “We look for the optimal spot on the brain that gives us the maximal engagement of the right networks that drive memory.”

rTMS slows cognitive decline in a small Phase 2 trial

In the Phase 2 trial, 50 participants with mild to moderate Alzheimer’s were randomized into two groups, one receiving an active rTMS treatment and the other receiving a sham treatment. 

While all the participants underwent the 45-minute calibration session, only the treatment group received active rTMS throughout the rest of the study. The participants in the sham group received an inactive rTMS treatment designed to look, sound, and feel like rTMS without actually zapping the brain. 

After the calibration, trial participants in both groups received 20-minute rTMS treatments daily for two weeks. Participants received one treatment session per week for the next 22 weeks of the trial. 

After 24 weeks, the participants who received active rTMS showed no decline on an 18-point standardized dementia scale, while those in the sham group declined by 1.3 points. A second study imaged the brains of 16 of the participants in the study, finding that the treatment also slowed brain shrinkage and improved the strength of the default mode network.  

Only eight people experienced side effects, like headache, skin discomfort, or neck stiffness. All of these side effects were mild, and none lasted longer than a day.

Limitations of the Phase 2 trial

Sinaptica’s website touts the treatment as a “true breakthrough” with “unprecedented” results. Mariash said the company describes the treatment as a breakthrough because it received a Breakthrough Device Designation from the FDA. This doesn’t actually mean that the treatment has been proven to be a breakthrough, but a designation given to promising medical devices that help speed up the regulatory process.

 “We describe the data as unprecedented because when we look at the entire landscape of Alzheimer’s treatments in development, monitoring the space for 20 years, we’re not aware of Phase 2 results for any drug or device with this magnitude of efficacy across all relevant primary and secondary endpoints,” Mariash added.

Mark George, a professor at the Medical University of South Carolina who is an expert in rTMS, and isn’t involved with Sinaptica, wasn’t entirely convinced. 

George said that methodological issues in the trial could have created biased results. 

The study wasn’t fully blinded, meaning that some people working on the study knew who was in the treatment group and who was in the placebo group, creating the opportunity for bias. Further, it only involved a small group of patients at one trial site. In part for these reasons, George said he personally would not use adjectives like “breakthrough” or “unprecedented” to describe the results.

“There have been lots and lots of false starts with Alzheimer’s disease treatments,” he added.

What’s next for Sinaptica

Sinaptica is designing a larger Phase 3 trial, including measurements of Alzheimer’s biomarkers, to determine whether the rTMS treatment is effective. It may be a few years until we know whether this approach works.