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 Previous work has shown that sleep abnormalities are associated with Alzheimer’s Disease (AD) in multiple ways, including the observation that sleep disruptions precede the onset of cognitive symptoms in AD subjects, and that there is a strong association between disrupted sleep and development and progression of AD (Ju et al, Nat Rev Neurol. 2014 Feb; 10(2): 115‐119, Lim et al, Neurodegener Dis Manag. 2014; 4(5):351‐362). These associations, along with the fact that sleep disturbances can have broad behavioral effects, have led to the suggestion that improving sleep is an important aspect of therapeutic strategies for subjects with AD. In the present study, the long‐term effects of non‐invasive gamma sensory stimulation (Cognito Therapeutics, Inc) on sleep were evaluated in mild to moderate AD patients. Method Activity of mild to moderate AD patients was monitored continuously with a wrist worn actigraphy watch, and data was collected during a 6‐month period. Patients were randomized to receive either 40Hz non‐invasive audio‐visual stimulation or placebo treatment. The durations of rest periods during the night was estimated from the actigraphy data and the distributions of these durations were compared between the first 3 months of the treatment period and the second 3 months of the treatment period in both cohorts. Result Analysis of the actigraphy data revealed that sensory‐evoked gamma stimulation improved sleep as assessed by continuous actigraphy recordings. In the active treatment group, the distribution of rest‐durations was shifted towards longer durations in the second 3 months compared with the first 3 months. In the placebo group the reverse was observed: the distribution of rest periods was shifted to shorter durations compared in the second 3 months to the first 3 months. The overall total sleep‐time at night was unaltered in either group. Conclusion Gamma stimulation therapy over six months demonstrated an improvement in sleep quality and increased night‐time restful periods as assessed by continuous actigraphy recordings.

Background: Daily, at-home gamma sensory stimulation consisting of EEG-calibrated auditory and visual stimuli is a new therapeutic approach for the treatment of Alzheimer's Disease (AD). Based on experimental studies demonstrating that sensoryevoked gamma oscillation halts or reverses AD-related pathology, improves cogni-