GENUS Stimulation to Prevent Alzheimer's Disease

Recruiting in Palo Alto (17 mi)

+1 other location

Overseen by Diane Chan, MD PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: Massachusetts General Hospital

Must not be taking: NMDA antagonists, Warfarin

Disqualifiers: Epilepsy, Renal disease, Seizure, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests a light and sound device that creates brain waves at 40Hz. It targets people aged 55+ with a family history of Alzheimer's disease. The device aims to boost brain waves to reduce harmful proteins and improve memory.

Will I have to stop taking my current medications?

The trial requires that participants do not take NMDA antagonists. If you are undergoing a lumbar puncture, you cannot use warfarin or similar blood thinners. Other medications are not specifically mentioned, so check with the study team for more details.

What data supports the effectiveness of the treatment GENUS, Gamma Entrainment Using Sensory stimulation, 40Hz Light and Sound Stimulation, in preventing Alzheimer's disease?

Research shows that GENUS, which uses 40Hz light and sound stimulation, can reduce Alzheimer's disease markers like amyloid and tau in mice, and improve memory and daily activities in humans with mild Alzheimer's. Studies also found that this treatment is safe, well-tolerated, and can improve brain connectivity and reduce brain shrinkage in patients. ^{1 2 3 4 5}

Is GENUS (Gamma Entrainment Using Sensory stimulation) safe for humans?

Studies show that GENUS, which uses 40Hz light and sound stimulation, is generally safe and well-tolerated in humans, including those with mild Alzheimer's disease. Participants in trials experienced no significant adverse effects, and the treatment was well-received over periods of up to six months. ^{1 2 3 4 6}

How is the GENUS treatment different from other Alzheimer's treatments?

GENUS is unique because it uses non-invasive sensory stimulation with light and sound at 40Hz to improve brain function and reduce Alzheimer's disease markers, unlike traditional drug treatments. This approach aims to restore normal brain rhythms and improve cognitive and daily living activities without medication. ^{1 2 3 4 7}

Eligibility Criteria

This trial is for cognitively normal people aged 55-90 with a family history of Alzheimer's, who have certain scores on memory and mental state exams, and specific brain amyloid levels. They must be able to undergo MRI/PET scans, have good vision and hearing for tests, and can't be pregnant or have severe illnesses that affect study participation.

Inclusion Criteria

Able to comply with neuropsychological testing and other study procedures in opinion of site PI

My immediate family has a history of Alzheimer's disease.

Delayed Recall score on the Logical Memory IIa subtest of 8 to 15 at baseline or expected score range for cognitively normal adjusted for education level

Exclusion Criteria

Laboratory findings, if known (study does not perform testing) suggestive of systemic illness such as renal disease

I have a brain condition like fluid buildup or a tumor.

I don't have bleeding disorders or low platelet levels if I agree to undergo a lumbar puncture.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants use the GENUS light and sound device at home for 12 months, 60 minutes each day

12 months

4-6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• GENUS (Behavioural Intervention)

Trial Overview The GENUS device uses light and sound at 40Hz to stimulate gamma waves in the brain. The study aims to see if this stimulation can prevent dementia in those at risk for Alzheimer's by reducing toxic proteins in the brain associated with memory loss.

Participant Groups

Group I: Active GENUS light and sound Active Control 1 Intervention

The device is a light and sound device that delivers light stimulation using light-emitting diodes (LED) and sound stimulation through a speaker, with a centrally-mounted tablet that plays videos for entertainment. The device will be positioned on an easel such that the tablet is eye level with the participant while they are sitting 5 feet away. The active device delivers light and sound at 40Hz rate.

Group II: Sham GENUS light and sound Placebo Group 1 Intervention

The device is the same as the active device but it delivers light and sound at different frequencies.

GENUS is already approved in United States for the following indications:

🇺🇸 Approved in United States as GENUS for:

• Investigational for prevention of dementia in people at risk for Alzheimer's disease

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Massachusetts Institute of Technology Cambridge, MA

Massachusetts General Hospital Boston, MA

Who Is Running the Clinical Trial?

Massachusetts General Hospital Lead Sponsor

Massachusetts Institute of Technology Collaborator

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

An update on the use of gamma (multi)sensory stimulation for Alzheimer's disease treatment. [2023] Alzheimer's disease (AD) is characterized by reduced fast brain oscillations in the gamma band (γ, > 30 Hz). Several animal studies show that inducing gamma oscillations through (multi)sensory stimulation at 40 Hz has the potential to impact AD-related cognitive decline and neuropathological processes, including amyloid plaques deposition, neurofibrillary tangles formation, and neuronal and synaptic loss. Therefore Gamma Entrainment Using Sensory stimulation (GENUS) is among the most promising approaches for AD patients' treatment. This review summarizes the evidence on GENUS effectiveness, from animal models to AD patients. Despite the application on human is in its infancy, the available findings suggest its feasibility for the treatment of AD. We discuss such results in light of parameter improvement and possible underlying mechanisms. We finally emphasize the need for further research for its development as a disease-modifying non-pharmacological intervention.

2. Switzerland pubmed.ncbi.nlm.nih.gov

Sensory-Evoked 40-Hz Gamma Oscillation Improves Sleep and Daily Living Activities in Alzheimer's Disease Patients. [2021] Pathological proteins contributing to Alzheimer's disease (AD) are known to disrupt normal neuronal functions in the brain, leading to unbalanced neuronal excitatory-inhibitory tone, distorted neuronal synchrony, and network oscillations. However, it has been proposed that abnormalities in neuronal activity directly contribute to the pathogenesis of the disease, and in fact it has been demonstrated that induction of synchronized 40 Hz gamma oscillation of neuronal networks by sensory stimulation reverses AD-related pathological markers in transgenic mice carrying AD-related human pathological genes. Based on these findings, the current study evaluated whether non-invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for AD patients. Patients with mild to moderate AD (n = 22) were randomized to active treatment group (n = 14; gamma sensory stimulation therapy) or to sham group (n = 8). Participants in the active treatment group received precisely timed, 40 Hz visual and auditory stimulations during eye-closed condition to induce cortical 40 Hz steady-state oscillations in 1-h daily sessions over a 6-month period. Participants in the sham group were exposed to similar sensory stimulation designed to not evoke cortical 40 Hz steady-state oscillations that are observed in the active treatment patients. During the trial, nighttime activities of the patients were monitored with continuous actigraphy recordings, and their functional abilities were measured by Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale. Results of this study demonstrated that 1-h daily therapy was well tolerated throughout the 6-month treatment period by all subjects. Patients receiving gamma sensory stimulation showed significantly reduced nighttime active periods, in contrast, to deterioration in sleep quality in sham group patients. Patients in the sham group also showed the expected, significant decline in ADCS-ADL scores, whereas patients in the gamma sensory stimulation group fully maintained their functional abilities over the 6-month period. These findings confirm the safe application of 40 Hz sensory stimulation in AD patients and demonstrate a high adherence to daily treatment. Furthermore, this is the first time that beneficial clinical effects of the therapy are reported, justifying expanded and longer trials to explore additional clinical benefits and disease-modifying properties of gamma sensory stimulation therapy. Clinical Trial Registration: clinicaltrials.gov, identifier: NCT03556280.

3. Netherlands pubmed.ncbi.nlm.nih.gov

Non-invasive auditory brain stimulation for gamma-band entrainment in dementia patients: An EEG dataset. [2022] Gamma entrainment has been shown to enhance beta amyloid (Aβ) uptake in mouse models of Alzheimer's disease (AD) as well as improve cognitive symptoms of dementia in both humans and mice. Similar improvements have been reported for both invasive and non-invasive brain stimulation in the gamma oscillatory band, with 40 Hz auditory and visual sensory stimulants employed in non-invasive approaches. Non-invasive stimulation techniques possess the clear advantage of not requiring surgical procedures and can hence be applicable to a wider set of patients. The dataset introduced here was acquired with the aim of examining the network-level mechanisms governing the production of the brain's oscillatory activity during non-invasive auditory gamma-band stimulation, and thereby helping to explain the reported therapeutic effects of entrainment in AD patients. Thirteen elderly participants with memory complaints whose conditions were diagnosed as normal aging (non-AD) or mild AD based on the standard criteria for the diagnosis of AD including the mini-mental state exam (MMSE) took part in data collection in which EEG signals were recorded during auditory stimulation of the brain. The data collection session consisted of an initial one-minute rest followed by an alternating set of six stimulation trials interleaved with five rest trials. During each stimulation trial, an auditory stimulant in the form of a 40 Hz chirp was presented to the participant. The collected data from all participants were preprocessed following the full pipeline of Makoto with the use of EEGLAB and posted as a dataset named: Auditory Gamma Entrainment at OpenNeuro repository. The data record for each participant includes the EEG signal represented in standard BIDS format for one-minute rest followed by the auditory task data. A copy of the source EEG data is also provided in .txt format. The dataset can be used to study the characteristics of brain oscillations during entrainment, as well as for studies on auditory perception, analysis of resting state potentials in dementia patients, comparison of auditory evoked potentials with resting state potentials, ERP, ERSP, and SSAVP analysis of auditory response in dementia patients, time series analysis of the stimulation and rest trials, and brain connectivity analysis in dementia patients.

4. United States pubmed.ncbi.nlm.nih.gov

Gamma frequency sensory stimulation in mild probable Alzheimer's dementia patients: Results of feasibility and pilot studies. [2023] Non-invasive Gamma ENtrainment Using Sensory stimulation (GENUS) at 40Hz reduces Alzheimer's disease (AD) pathology such as amyloid and tau levels, prevents cerebral atrophy, and improves behavioral testing performance in mouse models of AD. Here, we report data from (1) a Phase 1 feasibility study (NCT04042922, ClinicalTrials.gov) in cognitively normal volunteers (n = 25), patients with mild AD dementia (n = 16), and patients with epilepsy who underwent intracranial electrode monitoring (n = 2) to assess safety and feasibility of a single brief GENUS session to induce entrainment and (2) a single-blinded, randomized, placebo-controlled Phase 2A pilot study (NCT04055376) in patients with mild probable AD dementia (n = 15) to assess safety, compliance, entrainment, and exploratory clinical outcomes after chronic daily 40Hz sensory stimulation for 3 months. Our Phase 1 study showed that 40Hz GENUS was safe and effectively induced entrainment in both cortical regions and other cortical and subcortical structures such as the hippocampus, amygdala, insula, and gyrus rectus. Our Phase 2A study demonstrated that chronic daily 40Hz light and sound GENUS was well-tolerated and that compliance was equally high in both the control and active groups, with participants equally inaccurate in guessing their group assignments prior to unblinding. Electroencephalography recordings show that our 40Hz GENUS device safely and effectively induced 40Hz entrainment in participants with mild AD dementia. After 3 months of daily stimulation, the group receiving 40Hz stimulation showed (i) lesser ventricular dilation and hippocampal atrophy, (ii) increased functional connectivity in the default mode network as well as with the medial visual network, (iii) better performance on the face-name association delayed recall test, and (iv) improved measures of daily activity rhythmicity compared to the control group. These results support further evaluation of GENUS in a pivotal clinical trial to evaluate its potential as a novel disease-modifying therapeutic for patients with AD.

5. Netherlands pubmed.ncbi.nlm.nih.gov

Enhancement of the neural response during 40 Hz auditory entrainment in closed-eye state in human prefrontal region. [2023] Gamma-band activity was thought to be related to several high-level cognitive functions, and Gamma ENtrainment Using Sensory stimulation (GENUS, 40 Hz sensory combined visual and auditory stimulation) was found to have positive effects on patients with Alzheimer's dementia. Other studies found, however, that neural responses induced by single 40 Hz auditory stimulation were relatively weak. To address this, we included several new experimental conditions (sounds with sinusoidal or square wave; open-eye and closed-eye state) combined with auditory stimulation with the aim of investigating which of these induces a stronger 40 Hz neural response. We found that when participant´s eyes were closed, sounds with 40 Hz sinusoidal wave induced the strongest 40 Hz neural response in the prefrontal region compared to responses in other conditions. More interestingly, we also found there is a suppression of alpha rhythms with 40 Hz square wave sounds. Our results provide potential new methods when using auditory entrainment, which may result in a better effect in preventing cerebral atrophy and improving cognitive performance.

6. Switzerland pubmed.ncbi.nlm.nih.gov

Cognitive tasks propagate the neural entrainment in response to a visual 40 Hz stimulation in humans. [2022] Alzheimer's disease is one of the great challenges in the coming decades, and despite great efforts, a widely effective disease-modifying therapy in humans remains elusive. One particular promising non-pharmacological therapy that has received increased attention in recent years is based on the Gamma ENtrainment Using Sensory stimulation (GENUS), a high-frequency neural response elicited by a visual and/or auditory stimulus at 40 Hz. While this has shown to be effective in animal models, studies on human participants have reported varying success. The current work hypothesizes that the varying success in humans is due to differences in cognitive workload during the GENUS sessions.

7. France pubmed.ncbi.nlm.nih.gov

Gamma-patterned sensory stimulation reverses synaptic plasticity deficits in rat models of early Alzheimer's disease. [2023] Non-invasive sensory stimulation in the range of the brain's gamma rhythm (30-100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Here, we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long-term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)-overexpressing transgenic McGill-R-Thy1-APP rats at an early pre-plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease-relevant AD patient-derived synaptotoxic beta-amyloid and tau in wild-type animals. We found that daily treatment with 40 Hz sensory stimulation for 2 weeks fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase-1 in the hippocampus of transgenic APP animals, which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro-inflammatory mechanisms. Our findings support ongoing clinical trials of gamma-patterned sensory stimulation in early AD.