Gamma Light and Sound Stimulation to Prevent Dementia in Cognitively Normal People At Risk for Alzheimer's Disease

Not Applicable

Recruiting

• Conditions: Alzheimer Disease; Family Members
• Interventions: Device: GENUS

• Registration Number: NCT05776641
• Lead Sponsor: Massachusetts General Hospital

Brief Summary

Alzheimer's disease (AD) is characterized by significant memory loss, toxic protein deposits (amyloid and tau) in the brain, and changes in the gamma frequency band on EEG. Gamma waves are important for memory, and in patients with AD, there are fewer gamma waves in the brain. The Tsai lab found that boosting gamma waves in AD mouse models using light and sound stimulation at 40Hz not only reduced amyloid and tau in the brain, but also improved memory. A light and sound device was developed for humans that stimulates the brain at 40Hz that can be used safely at home. The goal of this study is to see if using this device can prevent dementia in people who are at risk for developing Alzheimer's disease.

Detailed Description

The investigators are recruiting participants aged 55+ with normal memory who have or had a close family member with Alzheimer's disease. 200 participants will undergo a blood test and a subset will undergo an amyloid PET scan and only 50 participants who have cerebral amyloid deposits will continue in the study. Neither the participant nor the investigators will know whether the participant is receiving sham or active stimulation. Participants will use the device for 12 months at home, for 60 minutes each day when they are awake. Participants will come to the Massachusetts General Hospital in Boston for 4-6 visits: before starting the stimulation, at 6 months, and after 12 months of usage. The participants will undergo PET scans, MRI, EEG, blood tests and memory tests and questionnaires at each visit to monitor progress. In addition, people may elect to allow for us to study their cerebral spinal fluid. Participants will also wear a "fitbit" like watch to monitor sleep and activity throughout the study. The goal of this study is to evaluate whether stimulation with our device at 40Hz will reduce AD pathology in the brain.

Study Timeline

• Study First Submitted: 2022-11-29
• Study First Submitted QC: 2023-03-08
• Study First Posted: 2023-03-20
• Study Start: 2024-01-10
• Status Verified: 2024-09
• Last Update Submitted: 2025-01-08
• Last Update Posted: 2025-01-10
• Primary Completion: 2026-05
• Study Completion: 2026-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 200

Inclusion Criteria

1. Between 55 - 90 years of age, inclusive.
2. Immediate family history of Alzheimer's disease.
3. Mini-Mental State Exam (MMSE) score of 27 or greater at baseline or expected score range for cognitively normal adjusted for education level.
4. Clinical Dementia Rating Global Score of 0 at baseline.
5. 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.
6. Low serum amyloid levels at baseline.
7. Elevated fibrillar amyloid using 11C PiB PET at baseline between 20 - 70 CL.
8. Willing and able to undergo MRI brain and PET brain scans.
9. Adequate visual and auditory acuity to allow for neuropsychological testing.
10. Able to comply with neuropsychological testing and other study procedures in opinion of site PI.
11. Willing and able to complete baseline assessments, and willing to participate in 13-month study protocol.
12. Willing to provide blood samples at specified timepoints. Willing to consider contributing CSF samples at specified timepoints, if asked.

Exclusion Criteria

1. MRI contraindications, such as presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments, or foreign objects in the eyes, skin, or body.

2. High myopia < -7 diopters, or untreated cataracts that affect vision.

3. Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the study protocol.

4. For subjects agreeing to undergo lumbar punctures, history of bleeding disorders or laboratory results indicating low platelet levels are exclusionary for the procedure.

5. Concomitant medications:

   1. Treatment with NMDA antagonists.
   2. For subjects undergoing lumbar puncture, current use of warfarin or similar anti-coagulants is exclusionary for the procedure.

6. Clinical conditions:

   1. History of seizure or medical diagnosis of epilepsy.
   2. Female subjects who are pregnant or currently breastfeeding.
   3. History of severe allergic or anaphylactic reactions.
   4. Longstanding premorbid history (i.e., longer than 10 years) of alcohol or substance abuse with continuous abuse up to and including the time that the symptoms leading to clinical presentation developed.
   5. Neurodegenerative disorder associated with cognitive impairment.
   6. Renal disease.

7. MR imaging findings such as stroke, tumor, leukoencephalopathy that could preclude meaningful analyses of clinical and imaging data in the opinion of the site PI, such as:

   1. Severe leukoencephalopathy seen on MRI.
   2. Relevant structural abnormality (i.e., normal pressure or obstructive hydrocephalus, hypoxic ischemic lesions, hemorrhages, tumors, malformations).
   3. Cerebral amyloid angiopathy, evidenced by T2* or other susceptibility weighted-MRI.

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

9. Site investigator's discretion, if s/he feels the subject cannot complete sufficient key study procedures. Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the Project Director.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active GENUS light and sound	GENUS	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.
Sham GENUS light and sound	GENUS	The device is the same as the active device but it delivers light and sound at different frequencies.

Primary Outcome Measures

Name	Time	Method
Changes in brain amyloid deposition over the study period, as measured by PiB PET.	Baseline to 12 months	The investigators will evaluate changes from baseline in amyloid deposition by using Pittsburgh compound B (PiB) PET, which is a standard for AD trial biomarkers, to assess progression towards AD with active or sham treatment.

Secondary Outcome Measures

Name	Time	Method
Changes to rest-activity parameters using actigraphy.	Baseline to 12 months	Actigraphy will be used to evaluate rest-activity parameters (ie, interdaily stability
Changes in brain electrical activity	Baseline to 12 months	The investigators will evaluate brain electrical activity using longitudinal EEG (ie, gamma band power)
Compliance of usage as measured by timestamp tracking and eye-tracking technology	Baseline to 12 months	The device contains both a time-counter to track 'on time' and a camera that records images for eye-tracking, to quantitatively determine compliance with looking directly at the device. This method also quantifies whether the subjects are awake for the duration of treatment. Previous work with healthy older adults and a small cohort of mild AD patients have had 90% compliance.
Change from baseline in CSF levels of amyloid and tau.	Baseline to 12 months	Lumbar puncture and CSF collection will be optional for participants, but will be informative as to the investigator's hypothesized mechanisms of clearance.
Changes in brain connectivity by functional MRI	Baseline to 12 months	The investigators will evaluate connectivity using resting state functional MRI to assess changes in brain networks (ie, default mode network).
Changes in brain tau deposition	Baseline to 12 months	The investigators will evaluate changes from baseline in tau deposition by using MK-6240 PET
Changes in brain structure using structural MRI	Baseline to 12 months	The investigators will evaluate changes in brain structure using structural MRI. Preliminary data show prevention of brain atrophy after 3 months of GENUS as measured by ventricular dilation and hippocampal volume. Using structural MRI, the investigators will evaluate brain volume, cortical thickness and ventricular volume.
Changes in blood biomarkers of AD	Baseline to 12 months	Changes in Alzheimer's blood-based biomarkers (e.g. plasma Aβ42/Aβ40 ratio, Aβ42, Aβ40, p-tau, and neurofilament light) assessed by longitudinal blood sample collection

Trial Locations

Locations (2)

Massachusetts Institute of Technology; 🇺🇸 Cambridge, Massachusetts, United States

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States