A medical device delivering auditory and visual stimulation that evoke a particular brain wave pattern is an encouraging nonpharmacologic option to treat symptoms of Alzheimer’s Disease (AD), a new phase 2 proof-of-concept study suggests.
“We showed daily gamma sensory stimulation is safe and well-tolerated, with beneficial effects in cognitive and functional abilities and a significant reduction in brain atrophy,” co-investigator Mihaly Hajos, PharmD, PhD, chief scientific officer, Cognito Therapeutics, and professor adjunct at Yale University School of Medicine, New Haven, Connecticut, told Medscape Medical News .
The device has already received Breakthrough designation from the US Food and Drug Administration (FDA).
The findings were presented at the 14th Clinical Trials on Alzheimer’s Disease (CTAD) conference.
Promising Target?
Previous research shows a bidirectional relationship between AD pathology and abnormal neuronal activity. This suggests that such abnormal neuronal activity, including aberrant oscillations, is a promising target for AD treatment, said Hajos.
The current study included 53 mostly White patients in their early 70s, with mild to moderate AD as measured by a score of 14 to 26 on the Mini-Mental State Examination (MMSE). Of these participants, 33 were randomly assigned to receive active stimulation and the other 20 received sham stimulation.
The active device delivers a combination of auditory and visual stimulations at a frequency of 40 Hertz (Hz) that elicit gamma oscillation in the brain as recorded by EEG.
“The combination stimulation is the most powerful way to induce oscillatory activity,” Hajos noted. Using just visual stimulation or just auditory stimulation “does not reach as broadly in the brain” to create the necessary oscillatory activity, he said.
In addition, experimental research has shown only the 40 Hz frequency elicits the desired brain wave activity. Higher and lower frequencies have been tested “but do not create the same biochemical, morphological, or cellular response,” said Hajos.
The sham stimulation was designed not to lead to gamma oscillation.
Researchers set up the device to deliver the stimulation. After that, patients took the device home and self-administered it for each 1 hour every day, ideally at the same time of day, for 6 months.
“Excellent” Safety Profile
From over 30,000 hours of treatment sessions, investigators determined the treatment had an “excellent” safety profile, with similar adverse events in the two groups, said Hajos. Treatment-emergent AEs that occurred more often in the active treatment group were tinnitus and headache.
Participants found it easy to incorporate the treatment into their regular daily schedule. with more than 80% adhering to the protocol, Hajos said.
“When the trial finished, we asked them if they wanted to take part in the open label extension and the vast majority wanted to continue using the device,” he added.
The intervention had the most profound effect on functioning, as shown on AD Cooperative Study Activities of Daily Living (ADCS-ADL) scores (P = .0009 vs sham).
“We saw this remarkable effect on activities of daily living, which in my view is a more important measure of how a patient is doing in their everyday life than remembering six words or five words” on the AD Assessment Scale-Cognitive subscale (ADAS-Cog), Hajos said.
There was somewhat of a mixed bag for cognitive function outcomes. Scores on the ADAS-Cog 14 and the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) were not significantly different between the two groups. However, there was a significant difference on the MMSE (P < .015) and the integrated AD Rating Scale (iADRS) (P < .03).
The active treatment also had an impact on the brain, as seen on MRI scans. It significantly lessened whole brain volume loss (P < .004), with a strong trend to reducing lateral ventricular expansion. In addition, there were significant reductions in loss of occipital lobe volume and in decline in cortical thickness.
Improved Sleep Quality
Actigraphy data in a subset of the participants showed that those in the active treatment group had improved sleep quality in terms of shorter periods of nighttime activity.
“This was in contrast to the placebo group where the pattern was the opposite — increased nighttime awake durations” Hajos reported.
“It’s very, very interesting to see this improvement in sleep quality because it’s well known that AD symptoms and pathology are closely linked to sleep abnormalities,” he said.
Hajos added he hopes to incorporate polysomnography into study assessments in the future. “It would be very interesting to go deeper and see how sleep structure is impacted or improved by the treatment,” he said.
The investigators are now planning a larger, multicenter phase 3 clinical trial to begin next year.
Encouraging Approach
Commenting on the study for Medscape Medical News, Heather Snyder, PhD, vice president of medical and scientific relations at the Alzheimer’s Association, said it is “encouraging” to see dementia researchers “taking new and different approaches” to investigate possible treatment strategies, such as this sensory stimulation and lifestyle approaches in addition to traditional drug therapies.
“Sensory stimulation and other noninvasive treatments for Alzheimer’s and other dementias have potential, and it is important to now evaluate these strategies in clinical trials, such as this presentation on the safety and tolerability of this approach,” Snyder said.
She noted the Alzheimer’s Association recently provided funding for another trial investigating this tool in a population at increased risk for AD and other dementias.
“We look forward to the continued evaluation of these approaches in the rigorous clinical trials needed,” Snyder said.
The study was funded by Cognito Therapeutics. Hajos is an employee of and owns equity in Cognito.
14th Clinical Trials on Alzheimer’s Disease (CTAD) conference: Abstract LB11. Presented November 12, 2021.
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