Neurotech Therapies Gain Prominence for Alzheimer’s

by James Cavuoto, editor

January 2024 issue

The neurotechnology market opportunity for treating Alzheimer’s disease has shown steady progress in recent months as several commercial firms and research organizations have reported advances. Some well publicized setbacks from pharmaceutical firms in this space have also contributed to a new sense of optimism for device interventions.

Many investigators and entrepreneurs in this space have chosen to challenge the prevailing thinking about amyloid beta and tau as causes of Alzheimer’s and instead look at the disease as an electrophysiological dysfunction, much like atrial fibrillation or epilepsy. And several research teams have honed in on stimulation frequencies in the gamma range, about 40 Hz, as a key part of their therapy.

One promising player in this market is Cognito Therapeutics, the Cambridge, MA neurotechnology startup developing disease-modifying therapies for neurodegenerative diseases. The company received a $73 million funding round last year.

“While several experimental drugs focus on addressing well-known amyloid plaques and tau tangles in the brain, Cognito is exploring an innovative, noninvasive medical device designed to target additional factors contributing to Alzheimer’s disease, by targeting abnormal electrical activities in the brain,” said Brent Vaughan, Cognito CEO. “This novel approach presents an opportunity to address Alzheimer’s disease using a different modality, offering a potential new treatment option for those affected by this devastating condition.”

Cognito recently announced publication of MRI imaging data from its Phase 2 OVERTURE study in the Journal of Alzheimer’s Disease. The paper, titled: “Noninvasive gamma sensory stimulation may reduce white matter and myelin loss in Alzheimer’s Disease,” reported that patients with mild-moderate Alzheimer’s disease who received one-hour daily treatment with Cognito’s gamma sensory device over six months showed reduced white matter atrophy and preserved brain myelin content compared to sham treatment in the study.

Cognito’s noninvasive neuromodulation platform was developed by MIT professors and scientific founders Li-Huei Tsai and Ed Boyden. The company’s lead therapy is currently in a pivotal study (HOPE) in Alzheimer’s disease and was awarded FDA breakthrough device designation.

The MRI treatment effect was highest in the entorhinal region, where white matter connections to the hippocampus are known to be involved in learning and memory and are affected in AD. These findings are consistent with preclinical data demonstrating that optogenetic-stimulated neuronal activity promotes oligodendrogenesis and myelin plasticity.

“The study results suggest that combined visual and auditory gamma-sensory stimulation may modulate neuronal network function in AD in part by reducing white matter atrophy and myelin content loss,” said Ralph Kern, CMO of Cognito Therapeutics. “The entorhinal region MRI outcomes may have significant implications for early AD intervention, considering the crucial afferent connections to the hippocampus and entorhinal cortex.”

White matter degeneration can affect brain function and connectivity, as myelin ensheathes axons and facilitates local and distant neuronal communication. Due to the crucial role of myelin in electrical impulse conduction within neuronal networks, longitudinal evaluation of white matter volume and myelin content could provide valuable insight into AD progression. Cognito therapy uses a proprietary noninvasive approach to induce increased gamma frequency brain activity via specific frequencies of auditory and visual neuromodulation.

“White matter atrophy and myelin loss may be a mechanistically important AD treatment target and may identify individuals at high risk of disease progression,” said Vaughan. “Our phase 2 OVERTURE study imaging results published in the Journal of Alzheimer’s Disease, show that our proprietary gamma sensory stimulation reduced white matter atrophy and preserved brain myelin content in patients. We look forward to advancing our Phase 3 HOPE study to bring this novel disease modifying therapy to patients.”

Brain function depends on continued maintenance of brain structural integrity. In AD, failure to maintain neuronal, synaptic, and myelin structures can affect neuronal network function and connectivity required to support cognition and daily function. Gamma frequency brain activity is essential for the maintenance of brain structure and function, and is impaired in AD. The evaluation of MRI, cerebrospinal fluid and plasma biomarkers in the HOPE biomarker substudy will provide key insights into AD progression and may help us see earlier predictive responses to Cognito therapy and may help us better identify patients and new disease areas that respond best to treatment.

A MIT study published in Nature at the end of 2016 helped to spur interest in the possibility that light flickering at the frequency of a particular gamma-band brain rhythm could produce meaningful therapeutic effects for people with Alzheimer’s disease. In a new review paper in the Journal of Internal Medicine, the lab that led those studies takes stock of what a growing number of scientists worldwide have been finding out since then in dozens of clinical and lab benchtop studies.

Brain rhythms arise from the synchronized, network activity of brain cells and circuits as they coordinate to enable brain functions such as perception or cognition. Lower-range gamma frequency rhythms, those around 40 Hz, are particularly important for memory processes, and MIT’s research has shown that they are also associated with specific changes at the cellular and molecular level. The 2016 study and many others since then have produced evidence initially in animals and more recently in humans that various non-invasive means of enhancing the power and synchrony of 40-Hz gamma rhythms helps to reduce Alzheimer’s pathology and its consequences.

“What started in 2016 with optogenetic and visual stimulation in mice has expanded to a multitude of stimulation paradigms, a wide range of human clinical studies with promising results and is narrowing in on the mechanisms underlying this phenomenon,” wrote the authors including Li-Huei Tsai, Picower professor in The Picower Institute for Learning and Memory and the department of Brain and Cognitive Sciences at MIT.

The authors list and summarize results from 16 clinical studies published over the last several years. These employ gamma frequency sensory stimulation (e.g. exposure to light, sound, tactile vibration, or a combination), transcranial alternating current stimulation, in which a brain region is stimulated via scalp electrodes, or transcranial magnetic stimulation, in which electric currents are induced in a brain region using magnetic fields. The studies also vary in their sample size, design, duration and in what effects they assessed. Some of the sensory studies using light have tested different colors and different exact frequencies. And while some studies show that sensory stimulation appears to affect multiple regions in the brain, tACS and TMS are more regionally focused (though those brain regions still connect and interact with others).

Another commercial firm pursuing the gamma frequency approach is Sinaptica Therapeutics, which uses magnetic stimulation rather than sensory stimulation. At the Neuroscience Innovation Forum in San Francisco earlier this month, Sinaptica CEO Ken Mariash described his company’s closed-loop TMS therapy. “Our sham-controlled published phase 2 results are better than what any drug has achieved,” he said. He downplayed the role of “usual suspects” tau and amyloid beta, equating them with the ashes after the house has burned down. Sinaptica’s therapy slowed the progression of Alzheimer’s by 80%, he said. Sinaptica’s therapy uses a single TMS pulse targeted at the percuneus structure in the brain in an effort to modulate the default mode network and then uses machine learning techniques to analyze EEG data resulting from the stimulation to produce an individualized therapeutic regimen for each patient.

Given the variances, the clinical studies taken together offer a blend of uneven but encouraging evidence, the Journal of Internal Medicine authors wrote. Across clinical studies involving patients with Alzheimer’s disease, sensory stimulation has proven safe and well tolerated. Multiple sensory studies have measured increases in gamma power and brain network connectivity. Sensory studies have also reported improvements in memory and/or cognition as well as sleep. Some have yielded apparent physiological benefits such as reduction of brain atrophy, in one case, and changes in immune system activity in another. So far, sensory studies have not shown reductions in Alzheimer’s hallmark proteins, amyloid or tau.

Clinical studies stimulating 40 Hz rhythms using tACS, ranging in sample size from only one to as many as 60, are the most numerous so far and many have shown similar benefits. Most report benefits to cognition, executive function and/or memory (depending sometimes on the brain region stimulated) and some have assessed that benefits endure even after treatment concludes. Some have shown effects on measures of tau and amyloid, blood flow, neuromodulatory chemical activity, or immune activity. Finally a 40Hz stimulation clinical study using TMS in 37 patients found improvements in cognition, prevention of brain atrophy and increased brain connectivity.

“The most important test for gamma stimulation is without a doubt whether it is safe and beneficial for patients,” the authors wrote. “So far, results from several small trials on sensory gamma stimulation suggest that it is safe, evokes rhythmic EEG brain responses, and there are promising signs for AD symptoms and pathology. Similarly, studies on transcranial stimulation report the potential to benefit memory and global cognitive function even beyond the end of treatment.”

Before MIT’s original studies in 2016 and 2019 researchers had not attributed molecular changes in brain cells to changes in brain rhythms, but those and other studies have now shown that they affect not only the molecular state of neurons, but also the brain’s microglia immune cells, astrocyte cells that play key roles in regulating circulation and indeed the brain’s vasculature system. A hypothesis of Tsai’s lab right now is that sensory gamma stimulation might promote the clearance of amyloid and tau via increased circulatory activity of brain fluids.

A hotly debated aspect of gamma stimulation is how it affects the electrical activity of neurons and how pervasively. Studies indicate that inhibitory “interneurons” are especially affected, though, offering a clue about how increased gamma activity, and its physiological effects, might propagate.