Abstract
Gamma entrainment using sensory stimulation (GENUS) is a noninvasive approach under investigation in older adults with and without cognitive impairment, including Alzheimer's disease; however, human evidence remains scattered across structural, functional, biomarker, electrophysiological, and cognitive domains. We searched PubMed, Embase, Scopus, and Web of Science for English-language articles published from January 2016 to December 2025, following PRISMA 2020 guidelines and a retrospectively registered PROSPERO protocol. Eligible studies evaluated non-invasive sensory gamma-frequency stimulation in adults aged ≥ 60 years, including Alzheimer's disease-spectrum and cognitively normal older adults, with quantitative outcomes reported in at least one relevant domain. Narrative synthesis was the primary approach, supplemented by an exploratory random-effects meta-analysis of hippocampal and ventricular volume change. Eight studies were included, spanning single-session to 6-month interventions. Findings were directionally favorable across domains but derived from small, heterogeneous studies with nonoverlapping outcomes. Fluid biomarker evidence was limited to exploratory immune-related findings from a single uncontrolled study. Controlled structural studies suggested possible attenuation of hippocampal atrophy, ventricular enlargement, and white matter decline. Functional connectivity findings suggested possible preservation of connectivity in Alzheimer's disease-relevant networks. Electroencephalography studies supported target engagement, with entrainment strength and propagation varying according to stimulation parameters and individual characteristics. Cognitive findings from small exploratory studies did not establish a consistent benefit. Exploratory pooled effects for ventricular and hippocampal volume change were favorable but not robust to conservative sensitivity analysis. Human evidence for GENUS is promising but preliminary and hypothesis-generating; larger, adequately powered, standardized trials are needed before firm efficacy conclusions can be drawn.