Modulation of Cortical and Hippocampal Functional MRI Connectivity Following Transcranial Alternating Current Stimulation in Mild Alzheimer Disease

Background Transcranial alternating current stimulation (tACS) may be effective for improving cognitive function in Alzheimer disease (AD), but its impact on brain functional connectivity (FC) has not been well studied. Purpose To evaluate tACS efficacy in improving cognitive performance and modulating FC between brain regions in individuals with AD using functional MRI. Materials and Methods In this prospective randomized controlled trial (September 2020 to April 2022), participants with mild AD were assigned to active (40 Hz tACS with 15-mA intensity) or sham (no γ frequency or current) tACS groups for 3 weeks (referred to as week 3), with a 3-month follow-up (referred to as month 3). Functional MRI and cognitive testing were performed at baseline, week 3, and month 3. Primary outcomes were changes in Mini-Mental State Examination and Montreal Cognitive Assessment scores from baseline to week 3. Secondary outcomes included FC changes within multiple cortical networks and between cortex and hippocampus from baseline to week 3 and month 3, assessed using Fisher z-transformed correlation coefficient (hereafter, z score). Results Forty-six participants were randomized into the active group (n = 23; median age, 66 years; IQR, 62-69 years; 16 female participants) or the sham group (n = 23; mean age, 64 years; IQR, 61-69 years; 14 female participants). The active group had higher Mini-Mental State Examination (median score change, 2 [IQR, 1-5] vs 0 [IQR, -1 to 2]; P = .001) and Montreal Cognitive Assessment (median score change, 2 [IQR, 0-4] vs 0 [IQR, -1 to 2]; P = .03) scores than the sham group at week 3, respectively. Compared with the sham group, the active group had increased FC between left hippocampus and left middle cingulate gyrus (z score difference, 0.29; 95% CI: 0.17, 0.42; false discovery rate [FDR]-adjusted P < .001) and between the left hippocampus and the left middle frontal gyrus (z score difference, 0.16; 95% CI: 0.03, 0.29; FDR-adjusted P = .04) within the posterior default-mode network (z score difference, 0.40; 95% CI: 0.07, 0.73; FDR-adjusted P = .046) and within the visual network (z score difference, 0.45; 95% CI: 0.17, 0.73; FDR-adjusted P = .007) from baseline to week 3. Conclusion Cognitive performance in mild AD improved following tACS, with increased FC within cortical networks and between the hippocampus and specific cortical regions. ClinicalTrials.gov Identifier: NCT03920826 © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Shepherd in this issue.