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.

Background Non‐invasive gamma sensory stimulation has been demonstrated to have beneficial effects on the hallmarks of AD pathophysiology in transgenic mouse models of AD. The Etude clinical trial is a translational clinical study examining dose‐ranging, safety, tolerability, and potential benefits of gamma sensory stimulation as a novel, non‐invasive treatment for Alzheimer’s disease. Method Two cohorts were planned to evaluate tolerability, safety and therapeutic effects by dose with results from the first cohort guiding dose escalation for the second. In the first cohort, 10 subjects were randomized to receive once or twice daily therapy for 12 months. When therapy was completed, safety and tolerability, as well as symptom progression, was evaluated and the second cohort was initiated; 3 subjects were enrolled at twice daily 1‐hour therapy for 12 months. All subjects received 40Hz audio‐visual therapy (Cognito Therapeutics, Cambridge MA) at home with assistance from a caregiver. Key criteria for subject enrolment were: adults 50 years and older, MMSE 24‐30, MCI due to AD diagnosis per NIA‐AA criteria, and an amyloid‐positive PET scan. Subjects were excluded for history of seizure, memantine use, alternate causes of cognitive impairment or MRI findings that prevented PET SUVr processing. Subjects were followed for safety, tolerability and changes to symptoms via clinical assessments, phone assessments, and electronic treatment diary. Tolerability was measured by device use, including treatment diary and device‐reported data, Zarit burden interview, and structured interviews at pre‐planned time points. Clinical progression was measured using MMSE, ADAS‐Cog, CDR, NPI, Clock‐Drawing Test, ADL, and QOL. Quantitative EEG, actigraphy, amyloid PET, volumetric MR are evaluated at regular intervals throughout the study as biomarkers. Result Thirty‐seven subjects were screened and 13 enrolled, of whom none terminated early and 3 are still active. An open‐label extension year was added to the protocol and 70% of subjects chose to re‐enroll. Review of MR imaging noted no ARIA and there were no unexpected related serious adverse events. Results on symptomatic and biomarker changes are being analyzed. Conclusion We describe the design and methods of a translational dosing study which evaluates a novel therapeutic modality. All evaluated dosing regiments were safe and well‐tolerated by subjects.

Background Non‐invasive, visual and auditory gamma (40 Hz) sensory stimulation demonstrates clearance of β‐amyloid plaques and tau tangles, and cognition improvement in preclinical AD models (Iaccarino, 2016, Martorell, 2019). A home‐use gamma sensory stimulation device (Cognito Therapeutics, Inc., Cambridge, MA) was developed to evoke gamma oscillations in humans. The long‐term safety and feasibility of this approach has not been previously evaluated in AD subjects. Method Overture is a prospective 6‐month treatment study in mild‐to‐moderate AD of the Cognito device. Subjects were randomized 2:1, treatment:sham. All subjects underwent in‐clinic EEG to confirm gamma entrainment and calibrate the device. Therapy was self‐administered daily during 1‐hour sessions at home with adherence logged by device. Safety assessments included adverse event (AE) monitoring, MRIs, and physical exams. Subjects and caregivers participated in multiple in‐depth interviews to assess the feasibility of this novel therapy. Subjects had the option to enter a 12‐month extension. Result In total, 20,562 treatment sessions have been completed by 74 subjects in the Main and Extension period. Overall rates of AEs during the Main and Extension study periods were roughly equivalent between groups (Active: 2.5/subject, Sham: 2.9/subject). There were no unexpected serious treatment emergent adverse events. Review of MR imaging data by neuroradiology demonstrated stable findings from baseline to follow‐up and absence of ARIA in all subjects. Adherence data showed that Sham participants had a final mean adherence of 95.9%±9.0%, while treatment participants had a final mean adherence of 90.2%±13.3%, and the difference was not significant in an independent‐samples, two‐tailed t‐test (p=0.14). Participants easily adopted and adhered to daily self‐administered therapy, with 60% of enrolled participants choosing to continue into the extension. Conclusion The interim results of the study demonstrate that long‐term, daily, self‐administered, home‐use of gamma sensory stimulation is both safe and well tolerated in mild‐to‐moderate AD subjects.

BackgroundAlthough white matter atrophy is observed in normal aging, it is more pronounced in Alzheimer’s Disease (AD) patients. Recently, advanced magnetic resonance imaging (MRI) provided more detailed information which linked changes in white matter to elevated risk and progression of AD. White matter degeneration, myelin loss, and oligodendrocyte damage in AD patients suggest that white matter can be a mechanistically important target in AD patients. Recently, clinical benefits of 40Hz gamma sensory stimulation have been demonstrated in AD patients. Here, we studied the effects of 40Hz gamma sensory stimulation on white matter in patients with clinical presentation of AD spectrum and compared our results to historical data.MethodThe data presented here is from Overture study (NCT03556280) and the Alzheimer's Disease Neuroimaging Initiative (ADNI1) database. Overture study data included treatment group participants who received 1‐hour daily 40Hz gamma auditory‐visual stimulation at home for a 6‐month period and placebo group. Analysis between the groups suggested a difference in white matter atrophy favoring the treatment group. To compare our treatment group with a larger control group, we studied ADNI1. We included a subset of each population so that baseline distributions (age, MMSE, white matter volume) are matched and had Month 6 MRI data. The resulting populations contained N=16 participants from Overture study and N=64 participants from ADNI1. Overture study structural MRI were acquired using 1.5 Tesla MRI and cerebral white matter segmentation was performed using FreeSurfer as it was done in ADNI1. Age, MMSE, white matter volume adjusted least‐square means method is used to assess the percentage changes in white matter volume within 6‐month period.ResultThe Overture study treatment group participants exhibited 0.38±0.82 percentage increase (volume in % of total intracranial volume) and ADNI1 study participants exhibited ‐2.45±0.40 percentage decrease in white matter volume after 6‐month period (p<0.004).ConclusionOur results suggest that 40Hz gamma sensory stimulation therapy for 6‐month period may reduce white matter atrophy, protect axons, and possibly prevent myelin and oligodendrocyte damage in AD patients. Given the crucial role of white matter connecting expansive brain regions, preventing or reducing its atrophy may diminish AD disease progression.

Background Preclinical studies in transgenic mice demonstrated that sub‐chronic 40 Hz gamma sensory stimulation effectively halted or reversed AD‐related pathology, increased synaptic density, improved cognitive function, and normalized circadian rhythm. The OVERTURE clinical trial (NCT03556280), funded by Cognito Therapeutics Inc., is a 2‐to‐1 randomized placebo‐controlled trial conducted to determine the safety, tolerability, and impact of gamma sensory stimulation on Alzheimer’s disease symptoms and biomarkers in humans. Method This US‐based 4‐site feasibility trial evaluated safety, tolerability, cognitive and functional symptoms, and biomarkers of target engagement, neurodegeneration, and AD pathology. The trial was conducted between June 2018 and July 2020. Participants age 50 and older with a diagnosis of mild‐to‐moderate Alzheimer’s disease (MMSE 14‐26) were randomly assigned (2‐to‐1: active‐control) to receive 6 months of 1‐hour daily 40 Hz audio‐visual or sham stimulation. Therapy was self‐administered at home with the help of a care partner, and patients, care partners, and assessment raters were blinded to group assignment. Result A total of 135 subjects were screened, of whom 74 (55%) were randomized and 53 completed (72%). Safety was evaluated by MRI, a suicidality scale, and physical and neurological exams at baseline, 12‐, and 24‐weeks, and monthly assessments of adverse events. Tolerability was measured by device use data, daily diary, and user experience interviews. Symptomatic changes were assessed daily via a diary, monthly via ADL, QOL, and care partner burden scales, and quarterly via the ADAS‐Cog14, NPI, CDR, and Clock Drawing Test, and the MMSE at baseline and week 24. Biomarkers, including Amyloid PET, Plasma amyloid‐β1‐42, ptau217, GFAP, and Neurofilament light, EEG, and volumetric MRI were examined at 3‐month increments. APOE status was characterized at baseline. Actigraphy devices were worn continuously throughout the trial to assess daytime and nighttime activity. Conclusion This feasibility trial is designed to demonstrate gamma sensory stimulation’s safety and tolerability, feasibility of daily in‐home use for AD patients, possible functional and symptomatic benefits, and both standard and novel biomarkers of AD pathology and neurodegenerative decline. Data will help inform the design of a larger study, including the development of patient selection algorithms, novel outcome measures and evidence of clinical efficacy.