Impact of 40 Hz Transcranial Alternating Current Stimulation on Cerebral Tau Burden in Patients with Alzheimer’s Disease: A Case Series1

Abstract

Background: Alzheimer’s disease (AD) is characterized by diffuse amyloid-β (Aβ) and phosphorylated Tau (p-Tau) aggregates as well as neuroinflammation. Exogenously-induced 40 Hz gamma oscillations have been showing to reduce Aβ and p-Tau deposition presumably via microglia activation in AD mouse models. Objective: We aimed to translate preclinical data on gamma-induction in AD patients by means of transcranial alternating current stimulation (tACS). Methods: Four participants with mild-to-moderate AD received 1 h of daily 40 Hz (gamma) tACS for 4 weeks (Monday to Friday) targeting the bitemporal lobes (20 h treatment duration). Participant underwent Aβ, p-Tau, and microglia PET imaging with [11C]-PiB, [18F]-FTP, and [11C]-PBR28 respectively, before and after the intervention along with electrophysiological assessment. Results: No adverse events were reported, and an increase in gamma spectral power on EEG was observed after the treatment. [18F]-FTP PET revealed a significant decrease over 2% of p-Tau burden in 3/4 patients following the tACS treatment, primarily involving the temporal lobe regions targeted by tACS and especially mesial regions (e.g., entorhinal cortex). The amount of intracerebral Aβ as measured by [11C]-PiB was not significantly influenced by tACS, whereas 1/4 reported a significant decrease of microglia activation as measured by [11C]-PBR28. Conclusion: tACS seems to represent a safe and feasible option for gamma induction in AD patients, with preliminary evidence of a possible effect on protein clearance partially mimicking what is observed in animal models. Longer interventions and placebo control conditions are needed to fully evaluate the potential for tACS to slow disease progression.

The role of gamma oscillations in central nervous system diseases: Mechanism and treatment

“…Patients with mild cognitive impairment (MCI) receiving 1-hour daily 40 Hz audiovisual stimulation for 4-8 weeks validated GENUS as a safe and tolerable treatment, while the participants demonstrated improved connectivity between posterior cingulate cortex and precuneus lobe, and decreased level of several cytokines such as TGF-α, MIP-1β, IL-5 and TNF-like weak inducer of apoptosis (TWEAK) in cerebrospinal fluid, though Aβ and tau load remained unchanged (He Q. et al, 2021). Likewise, 40 Hz tACS treatment had no significant influence on Aβ burden but a moderate decrease of p-Tau in the targeted temporal lobe (Dhaynaut et al, 2022). Using 125Hz fast-gamma magnetic stimulation (FGMS) in patients with AD and MCI, the results showed no significant amelioration in cognition and depression (Mimenza-Alvarado et al, 2021).…”

Transcranial alternating current stimulation combined with sound stimulation improves the cognitive function of patients with Alzheimer's disease: A case report and literature review

“…As gamma oscillations are closely related to cognitive function, they are impaired in multiple AD models (30). Approximately 40 Hz is the stimulation frequency used in this experiment because, in previous studies, it has been found that 40-Hz light flicker or 40-Hz tone flickering is applied to an animal or 40-Hz tACS is applied to a patient with AD can improve cognitive function and decrease amyloid and phosphorylated tau levels (13,31,32). The role of gamma frequency (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48) in advanced cognitive processes (including attention, learning, and memory) has been studied (33,34).…”

Local and Distributed fMRI Changes Induced by 40 Hz Gamma tACS of the Bilateral Dorsolateral Prefrontal Cortex: A Pilot Study

“…In particular, animal studies have revealed that the induction of γ frequency activity through sensory stimulation or optogenetics reduces amyloid- β plaques [ 78 , 79 ], as well as that optogenetic modulation of parvalbulmin (PV+) and somatostatin (SST+) interneurons restores γ oscillations in murine models of AD [ 80 ]. Preliminary evidences are also arising from pilot studies using 40 Hz tACS in AD patients [ 81 , 82 ].…”