Novel Therapeutic Approach Improves Episodic Memory in Alzheimer Disease

Application of γ-tACS over the precuneus can enhance episodic memory in patients with early Alzheimer disease.

The use of transcranial alternating current stimulation at gamma-frequency (γ-tACS) applied over the precuneus region of the brain may represent a novel therapeutic approach for the treatment of patients with Alzheimer disease (AD), according to the study findings published in the Annals of Neurology.

Researchers sought to evaluate whether exposure to γ-tACS that targets the precuneus is associated with improvements in the performance of episodic memory performances, as well as restoration of intracortical excitability measures of cholinergic neurotransmission, compared with the use of sham-tACS. They conducted a randomized, double-blind, sham-controlled, crossover study (Mod-GammAD; Identifier: NCT04842955) among participants who fulfilled the current criteria for AD who were recruited from the neurology unit, department of clinical and experimental sciences, University of Brescia in Italy.

At study enrollment, all of the individuals received a standardized neuropsychological assessment, a structural imaging study, and blood sampling for genotype analyses. The Italian version of the Cognitive Reserve Index, which is based on level of education, working activities, and leisure time, was used to assess the cognitive reserve among the participants. An AD diagnosis was established by either an analysis of cerebrospinal fluid that supported an AD pathologic process (ie, beta-amyloid [Aβ]1-42 ≤600 ng/L and tau ≥400 ng/L) or a positive amyloid-positron emission tomography scan.

A total of 60 participants (mean age, 72.3 years; 51.7% women; mean Mini-Mental State Examination [MMSE] score, SD = 23.9; mean disease duration, SD = 3.1years) underwent a clinical and neuropsychological assessment, which included an evaluation of episodic memory and cholinergic transmission prior to and following 60 minutes of treatment with γ-tACS targeting the precuneus or sham-tACS. A memory task that evaluated associative memory was performed during the last 20 minutes of tACS stimulation. In each session, a transcranial magnetic stimulation (TMS) protocol that evaluated short-latency afferent inhibition (SAI) — an indirect measure of cholinergic transmission — was carried out 2 times in each of the participants.

Response to γ-tACS was dependent on genetic factors and disease stage.

In a subset of 10 participants, an electroencephalogram was recorded 2 times in each session — that is, at baseline (prestimulation) and immediately after tACS (poststimulation) — prior to the TMS evaluation.

The researchers found a significant improvement in the Rey Auditory Verbal Learning (RAVL) test immediate recall (Estimate difference, -7.0 points; 90% CI, -8.2 to -5.8; P <.001) and RAVL delayed recall scores (Estimate difference, -1.6 points; -1.6; 90% CI, -2.0 to -1.2; P <.001) following application of γ-tACS but not following sham-tACS. Additionally, SAI increased following γ-tACS (Estimate difference, 0.35 points; 90% CI, 0.31 to 0.39; P <.001) but not after sham-tACS.

The best predictors of response to γ-tACS included apolipoprotein E (APoE) genotype and baseline cognitive impairment. Further, clinical improvement was associated with increases in gamma frequency in posterior regions and with the amount of predicted electric field distribution in the precuneus.

Several limitations of the current study should be noted. To begin, since the effects of a single session of γ-tACS over the precuneus were evaluated, long-term effects warrant assessment in multisession trials. Second, a larger, multicentric sample of participants might strengthen further the current results and account for any possible confounders.

“Response to γ-tACS was dependent on genetic factors and disease stage,” the researchers noted. They concluded that “Future studies with multisession γ-tACS and with at-home setting design are warranted.”

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Benussi A, Cantoni V, Grassi M, et al. Increasing brain gamma activity improves episodic memory and restores cholinergic dysfunction in Alzheimer’s disease. Ann Neurol. 2022;92(2):322-334. doi: 10.1002/ana.26411