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 Alzheimer’s disease (AD) patients exhibit distorted excitatory‐inhibitory balance of neuronal activity, leading to accelerated worsening of functional and cognitive abilities. Improving abnormal neuronal synchrony by long‐term non‐invasive, gamma sensory stimulation at 40 Hz in transgenic mice carrying pathological AD human genes has been shown to beneficially affect neural activity and improve learning and memory. In the present translational clinical trial, the effects of gamma sensory stimulation on cognition and global function were evaluated in AD patients using an at‐home therapy device (Cognito Therapeutics, Cambridge, MA). Method The phase I/II randomized, controlled, single‐blinded multi‐center clinical trial (Overture study; NCT03556280) evaluated safety, adherence rates and efficacy of gamma sensory stimulation therapy in patients with mild to moderate Alzheimer’s disease (MMSE 14‐26, inclusive). The 6‐month trial included treatment and sham groups receiving daily, one‐hour sensory stimulation but only participants in the treatment group were exposed to 40Hz auditory and visual stimulations. During the trial, cognitive functions were measured by Alzheimer's Disease Assessment Scale (ADAS‐Cog), Mini‐Mental State Examination (MMSE), and Clinical Dementia Rating Sum of Boxes (CDR‐SB). In order to align assessment data in time to study events (therapy start and end) and account for variable study visit intervals at start and end of therapy period, cognitive measures were calculated on a per‐patient basis by a model of AD‐related cognitive decline derived from a large‐scale dataset. Finally, adjusted cognitive scores were compared between the two groups. Result The trial has been completed by 33 and 19 patients in the treatment and sham groups, respectively. Daily therapy of gamma sensory stimulation was well tolerated, confirming safety and high adherence. The three independent cognitive tests demonstrated a diminished cognitive decline in the treatment group compared to the sham group. Final analysis results from MMSE, ADAS‐Cog, CDR‐SB and Integrated Alzheimer's Disease Rating Scale (iADRS) will be presented at the meeting. Conclusion The present findings, together with the established safety profile, functional benefit, and improvement in sleep justify further evaluation of gamma sensory stimulation in AD patients.