Gamma sensory stimulation in AD patients, a randomized controlled trial

Abstract

AbstractBackgroundPreclinical 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.MethodThis 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.ResultA 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.ConclusionThis 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.