Gamma Frequency Sensory Stimulation In Probable Mild Alzheimer'S Dementia Patients: Results Of A Preliminary Clinical Trial

Non-invasive Gamma ENtrainment Using Sensory stimuli (GENUS) at 40Hz reduced Alzheimer’s disease (AD) pathology, prevented cerebral atrophy and improved performance during behavioral testing in mouse models of AD. We report data from a safety study ([NCT04042922][1]) and a randomized, placebo-controlled trial in participants with probable mild AD dementia after 3 months of one-hour daily 40Hz light and sound GENUS ([NCT04055376][2]) to assess safety, compliance, entrainment and possible effects on brain structure, function, sleep and cognitive function. GENUS was well-tolerated and compliance was high in both groups. Electroencephalography recordings show that our GENUS device safely and effectively induced 40Hz entrainment in cognitively normal subjects and participants with mild AD. After 3 months of daily stimulation, participants with mild AD in the 40Hz GENUS group showed less ventricular enlargement and stabilization of the hippocampal size compared to the control group. Functional connectivity increased in both the default mode network and the medial visual network after 3 months of stimulation. Circadian rhythmicity also improved with GENUS. Compared to controls, the active group performed better on the face-name association delayed recall test. These results suggest that 40Hz GENUS can be used safely at home daily and shows favorable outcomes on cognitive function, daily rhythms, and structural and functional MRI biomarkers of AD-related degeneration. These results support further evaluation of GENUS in larger and longer clinical trials to evaluate its potential as a disease modifying therapeutic for Alzheimer’s disease. ### Competing Interest Statement LHT is a scientific co-founder, SAB member and Board of Director of Cognito Therapeutics. ESB is a scientific co-founder, SAB member of Cognito Therapeutics. ### Clinical Trial NCT04055376 ### Funding Statement We are thankful to the following individuals and organizations for their support of the work: The JPB Foundation, Robert A. and Renee Belfer, Halis Family Foundation, the Eleanor Schwartz Charitable Foundation, the Degroof-VM Foundation, Gary Hua and Li Chen, Lester Gimpelson, the Ludwig Family Foundation, David B. Emmes, Elizabeth K. and Russell L. Siegelman, Joseph P. DiSabato and Nancy E. Sakamoto, Alan and Susan Patricof, Jay L. and Carroll D Miller, Donald A. and Glenda G. Mattes, Marc Haas Foundation, Alan Alda, and Dave Wargo. Dr. Chan received support from the NIH Loan Repayment Program, Picower Fellowship and the Harvard Catalyst KL2/Catalyst Medical Research Investigator Training (CMeRIT) Award. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All studies were approved by the Committee on the Use of Humans as Experimental Participants (COUHES) at the MIT and the University of Iowa Institutional Review Board (IRB), respectively. These studies were carried out in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). All participants and their primary caregivers provided written informed consent before participation. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data are available in the main text or the supplementary materials. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04042922&atom=%2Fmedrxiv%2Fearly%2F2021%2F05%2F17%2F2021.03.01.21252717.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04055376&atom=%2Fmedrxiv%2Fearly%2F2021%2F05%2F17%2F2021.03.01.21252717.atom