A Focused Review of Gamma Neuromodulation as a Therapeutic Target in Alzheimer’s Spectrum Disorders

Abstract

The aging population of the world is increasing at an unprecedented rate which is expected to lead to a corresponding unparalleled increase in age related diseases. Of particular concern are the large number of older adults expected to develop Alzheimer’s disease (AD), which will require extraordinary local, national and worldwide healthcare resources. In this context, innovative interventions are needed urgently to delay AD onset and thereby give our healthcare systems time to prepare and provide meaningful care to our aging populations. This focused review discusses the crucial role of frontal gamma oscillations as a therapeutic target to delay or ameliorate cognitive decline in AD. Frontal gamma oscillations, including from prefrontal cortical areas, serve as a biomarker for working memory and other cognitive functions, and their impairment is observed before clinical symptoms manifest. This review evaluates evidence from animal models and human subjects to highlight the correlation between gamma wave abnormalities and cognitive deterioration. Furthermore, the review summarizes 11 clinical studies using neuromodulation techniques designed to stimulate gamma oscillations in mild cognitive impairment (MCI) and AD patients, including transcranial electrical stimulation, transcranial magnetic stimulation, and rhythmic sensory stimulation. These interventions have shown promise in mitigating early-stage cognitive decline, as evidenced by improved performance on memory tests, increased gamma oscillatory responses, and some have even shown reduced brain atrophy. These early studies suggest that treatments that strengthen frontal gamma oscillatory responses through neuromodulation are a promising approach to delay cognitive decline, that may serve as an adjunct to other therapies or as a standalone treatment in some populations.

Visually Evoked 40 Hz Gamma Activity Enhanced by Transcranial Electrical Stimulation

“…Oscillations in the gamma band (30-100 Hz, especially at 40 Hz) are of particular interest due to their role in perception and memory (Herrmann et al, 2010) and because they are disrupted in older age, cognitive impairment, and Alzheimer’s Disease (Güntekin et al, 2022). By modulating gamma activity, both VS and TES at this frequency are promising approaches to causally investigate memory functions (Hanslmayr et al, 2019) and to intervene against cognitive decline in dementia (Guan et al, 2022; Nissim et al, 2023; Shu et al, 2024; Strüber & Herrmann, 2020; Traikapi & Konstantinou, 2021). If multisensory stimulation yields larger effects than one modality alone (Blanco-Duque et al, 2023), combining sensory and electrical modalities is also likely to increase effects, but this approach is untested.…”