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INTRODUCTION: We evaluated the long-term effects of daily 40 Hz (gamma frequency) audiovisual stimulation on cognition and biomarkers in five patients with mild Alzheimer's disease (AD).METHODS: Over 2 years, patients received 1-h daily stimulation. Electroencephalography (EEG) was used to assess neural entrainment; magnetic resonance imaging (MRI) measured brain volumes; actigraphy monitored activity patterns; neuropsychological tests evaluated cognition; and S-PLEX assay measured plasma pTau217.RESULTS: No adverse events occurred over the study period. Three female patients with late-onset AD (LOAD) retained strong EEG entrainment and showed less decline in Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Functional Assessment Scale (FAS) scores compared to matched controls from National Alzheimer's Coordinating Center (NACC), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). Plasma samples were available for only two of five participants - both with LOAD - and both showed pTau217 reductions of 47% and 19%.DISCUSSION: These findings suggest that long-term 40 Hz audiovisual stimulation is safe, feasible, and may offer cognitive and biomarker benefits in some individuals with mild AD, supporting further investigation.CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT04055376).HIGHLIGHTS: Five mild Alzheimer's disease (AD) patients safely used daily 40 Hz audiovisual stimulation for 2 years. Late-onset AD (LOAD) patients showed increased 40 Hz electroencephalography (EEG) power and improved cognitive scores. National Alzheimer's Coordinating Center (NACC) data enhanced early-phase analysis and support precision medicine in AD studies. Plasma pTau217 declined in 2 LOAD patients after 2 years of daily use. This small pilot is the first to link long-term 40 Hz therapy to AD biomarker change.