Abstract
INTRODUCTION: Gamma oscillations in the brain are necessary for normal cognitive function, sensory processing, and memory consolidation, and are reduced in Alzheimer's disease (AD). In a 6 month, randomized, feasibility trial in participants with mild-to-moderate AD (OVERTURE [NCT03556280], n = 76), a non-invasive method for sensory-evoked brain gamma oscillations outperformed sham on the secondary outcomes of slowing decline on the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) functional scale, magnetic resonance imaging measures of whole brain volume and the Mini-Mental State Examination (MMSE) cognitive outcome, despite not showing statistical significance on the primary outcome (Mild and Moderate Alzheimer's Disease Composite [MADCOMS]), a composite cognitive-functional score. In this post hoc analysis of OVERTURE, we evaluated the effects of investigational sensory-evoked gamma oscillation treatment in terms of time saved, as an estimate of slowing in disease progression, on ADCS-ADL, MMSE, and whole-brain volume. METHODS: Disease trajectories based on the ADCS-ADL, MMSE, and whole-brain volume changes from baseline within each treatment group were constructed using mixed-effects models. Horizontal projection from active to sham arm yielded time saved from baseline at each visit. Data from the open label extension (OLE) phase of the OVERTURE study have also been used to analyze the time-saving effect of active treatment in an extended period. RESULTS: Compared to sham, time savings of 4.83, 4.59, and 4.09 months over 6 months of active treatment on ADCS-ADL, MMSE, and whole-brain atrophy were observed in the randomized controlled trial phase. When including the OLE phase, time savings of 8.66, 10.00, and 7.48 months over 14.64, 15.98, and 13.46 months of active treatment on ADCS-ADL, MMSE, and whole-brain atrophy were observed relative to the sham group. DISCUSSION: These findings suggest that further exploration of the effect of evoked gamma oscillations in participants with mild-to-moderate AD, as well as the evaluation of treatment effects using time saved, is merited. HIGHLIGHTS: Evoked gamma oscillation slows functional loss and brain atrophy in Alzheimer's disease.Slowing of functional and cognitive decline and brain atrophy worsening can be expressed as time saved.Evoked gamma oscillation saves 4.83 months of progression in activities of daily living, 4.59 months of progression in Mini-Mental State Examination, and 4.09 months of decline in whole-brain volume over 6 months.