GABAergic activity and gamma oscillations in Alzheimer’s disease and mild cognitive impairment: Neuropathology and therapeutic neuromodulatory insights from animal and human studies

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, carries one of the highest disability burdens of brain diseases. Disruptions in GABAergic activity and alterations in gamma oscillations are key pathological features of AD associated with amyloid-beta (Aβ) plaques. Although there are links between GABAergic activity and gamma oscillations in AD neuropathology, an updated and comprehensive synthesis of preclinical and human studies is needed to develop effective interventions. This review provides an updated overview of the literature published in 2005–2025 ( n = 127 studies) on GABAergic activity, gamma oscillations, and related therapeutic approaches in AD and mild cognitive impairment (MCI). The review is organized into two major sections covering: (1) GABAergic signaling in AD neuropathology and associated therapeutic approaches, and (2) gamma oscillations alterations in AD neuropathology and corresponding interventions. Each section summarizes findings from basic animal and human studies as well as intervention studies targeting GABAergic signaling or gamma oscillations in both preclinical models and human populations (AD/MCI). The preclinical models consistently characterize GABAergic dysfunction by selective loss and dysregulation of parvalbumin/somatostatin interneurons, imbalanced tonic–phasic inhibition, and network hyperexcitability, that are associated with memory deficits. Human studies with in vivo spectroscopy and post‑mortem data similarly report reduced GABA levels, altered receptor and transporter expression, and interneuronal vulnerabilities associated with cognitive and affective symptoms. Gamma oscillations—largely mediated by GABAergic interneurons—show disrupted power and coupling in AD models and human clinical populations, as a hallmark of network dysfunction. In preclinical interventional studies, targeting GABA and interneuron transplantation can restore inhibitory balance, reduce pathology, and improve cognition. Furtheremore, preclinical studies show that 40 Hz stimulation (light/sound, somatosensory, electrical, magnetic) engages microglia, modulates vascular—cerebrospinal fluid dynamics, reduces Aβ/tau burden, enhances long-term potentiation, and improves behavior. In humans, 40 Hz transcranial alternating current stimulation/transcranial magnetic stimulation over prefrontal cortex, temporo-parietal hubs, and precuneus, as well as non-focal multisensory stimulation (audiovisual), increases gamma power and connectivity and shows modest cognitive benefits, although amyloid positron emission tomography outcomes and glymphatic clearance effects are inconclusive. Both GABA and gamma‑based interventions appear safe and well-tolerated. Collectively, GABAergic deficits and gamma dysrhythmia form a bidirectional cascade in AD progression, supporting a synergistic intervention targeting both mechanisms. Current research gaps include limited longitudinal and multimodal biomarker datasets across disease stages, underpowered human trials, lacking sham controls and dose-response studies, and limited stratification and heterogeneous cognitive endpoints that hinder comparability and translation.