Brain Network Disorders Review Presents Mechanisms of Alzheimer’s Disease Progression
Restoring GABAergic circuit activity and Gamma oscillations protects the brain and slows cognitive impairment linked to Alzheimer’s Disease
image: Gamma neuromodulation activates GABAergic signaling, restoring neuronal activity related to memory and cognition, and protecting against further damage by amyloid beta plaques
Credit: Image Credit: Mohammed Ali Salehinejad from RWTH Aachen University, Germany Image Source Link: https://doi.org/10.1016/j.bnd.2026.01.002
Alzheimer’s Disease (AD) is the most common neurodegenerative disease across the globe. Accumulation of amyloid beta (Aβ) protein plaques and/or tau protein fibrils in the brain causes the progressive loss of memory and cognitive functions, and changes in behavior that are a hallmark of AD.
Studies have shown that these pathogenic proteins affect the Gamma Aminobutyric acid (GABA) ergic neuronal circuits and gamma oscillations within the brain. These dysfunctions are closely linked to the memory impairments characteristic of AD. “Gamma oscillations depend on the precise timing of GABAergic interneurons, particularly parvalbumin-positive interneurons, and their interaction with excitatory pyramidal neurons. When these rhythms are disrupted by Aβ or tau pathology, abnormal network synchronization can impair information flow and memory processes,” says Dr. Mohammad Ali Salehinejad of RWTH Aachen University.
Dr. Salehinejad and Dr. Ali Fathi Jouzdani of IPM Tehran conducted a comprehensive narrative systmetic review of the latest research on the correlations between GABAergic activity, gamma oscillations, and AD symptoms. Over 120 publications were included in this review. Their findings were made available online on January 30, 2026, in the journal Brain Network Disorders.
Within the GABAergic circuitry of the brain, certain classes of neurons are the first to be affected by AD-associated protein accumulation. These are the somatostatin (SST+) and calretinin (CR+) interneurons, which are then followed by parvalbumin (PV+) interneurons. Progressive loss of function of these classes results in poor synchronization of GABAergic neurons. This is worsened by dysfunctional astrocytes – immune cells found in the brain – which cause persistent inflammation around GABAergic neurons. Putting together, the order of this cascade coincides with the progressive loss of smell, followed by memory loss, seen in AD.
Gamma oscillations are high-frequency (30–100 Hz) sequences of cerebral activity, occurring during resting states in regions associated with smell, cognition, and homeostasis. Gamma oscillations are mediated by GABAergic interneurons. Therefore, Aβ or tau accumulation in these neurons affects gamma oscillations, causing them to lose synchrony, show abnormal excitation or inhibition. In turn, this demands more resources from the brain to try and restore gamma synchrony, making resting states transient and inadequate for proper brain function. Weakened resting-state gamma oscillations correlated with increased power of stimulus-induced gamma-oscillation, a sign of degrading brain tissue.
Clinical interventions targeting both mechanisms appear to reduce the severity and slow the progression of AD. Drugs that increase GABA receptor activity reduced cognitive impairment. Tissue examinations showed that these drugs slowed the accumulation of tau fibrils and made neurons less vulnerable to Aβ plaques. As a result, both animal AD models and human patients experienced mild improvements in memory and learning.
Similarly, 40 Hz external stimulations through multisensory protocols – flashing lights, sound, touch – reinforced resting state gamma oscillations and reduced the power of stimuli-induced oscillations. Transient alternating current stimulus (tACS) of 40 Hz also produced similar changes in gamma oscillations. More significantly these 40 Hz external stimulations reduced the amount of Aβ plaques. Human patients receiving stimulation therapy showed cognitive and functional improvements.
Considering the strong close relationship between GABAergic circuits and Gamma oscillations, Dr. Salehinejad believes that the nuances of both mechanisms should be incorporated into our understanding of AD. In addition, strategies that jointly target GABAergic signaling and gamma oscillatory activity may represent a promising direction for future AD interventions. “By combining GABAergic modulation with gamma-frequency stimulation, future approaches may move beyond symptomatic support toward mechanism-based neuroprotective strategies, while addressing key challenges related to personalization, dose optimization, and scalability,” he says.
While these findings have revealed encouraging insights into AD and novel approaches to treat its symptoms, Dr. Salehinejad sees the need to move from exploratory research to new diagnostic and treatment protocols. Population-level studies can help identify pathogenic variations in gamma oscillation power or markers related to GABAergic dysfunction. Early identification of these markers can help physicians identify the potential severity of AD in a patient and plan appropriate interventions.
Dr. Salehinejad hopes that, in time, new technologies will allow these interventions to be carried out at home easily and effectively, thus allowing many more patients with AD to benefit from GABAergic activation and gamma oscillation entrainment.
Reference
Titles of original papers: GABAergic activity and gamma oscillations in Alzheimer’s disease and mild cognitive impairment: Neuropathology and therapeutic neuromodulatory insights from animal and human studies
Journal: Brain Network Disorders
DOI: https://doi.org/10.1016/j.bnd.2026.01.002