Cognitive and Neuropsychiatric Effects of 40 Hz tACS Simultaneously with Cognitive Exercises for Dementia: A Randomized, Crossover, Double-Blind, Sham-Controlled Study

<i>Background and Objectives</i>: Transcranial alternating current stimulation (tACS) at 40 Hz has shown potential to enhance cognitive function. However, research on its combination with cognitive exercises, particularly its long-term effects in a dementia population, remains limited. This study investigated the effects of 40 Hz tACS paired with simultaneous cognitive exercises on cognition, neuropsychiatric symptoms, and the depression status of individuals with dementia in a sham-controlled, double-blind crossover design. <i>Materials and Methods</i>: A total of 42 participants with dementia were randomized into two groups: (1) the R1S2 group received 40 Hz real tACS with cognitive exercises, followed by a ≥8-week washout period, and then sham tACS with cognitive exercises; (2) the S1R2 group received the reversed sequence. tACS was applied at 1.5 mA peak-to-peak with electrodes over the left dorsolateral prefrontal cortex and contralateral supraorbital area. Participants received two 30 min stimulation sessions per day, 5 days per week, for 4 consecutive weeks, paired with cognitive exercises using the MindTriggers app (2.9.1). The primary outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the secondary outcomes included the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Neuropsychiatric Inventory Questionnaire (NPI-Q). All outcome measures were assessed before and after each treatment block. <i>Results</i>: Real tACS paired with cognitive exercises significantly improved ADAS-Cog scores post-treatment compared to pre-treatment (<i>p</i>-value = 0.019), whereas sham tACS did not. Furthermore, real tACS produced significant long-term improvements approximately 2-3 months post-treatment in ADAS-Cog scores compared to sham (<i>p</i>-value = 0.048). Both real (<i>p</i>-value = 0.003) and sham (<i>p</i>-value = 0.015) tACS significantly reduced NPI-Q scores post-treatment. MADRS scores significantly improved (<i>p</i>-value = 0.007) post-treatment for real tACS but not sham. <i>Conclusions</i>: The 40 Hz tACS paired with cognitive exercises improves cognition, neuropsychiatric symptoms, and depression post-treatment in dementia, with sustained cognitive effects. The findings highlight its potential as a non-invasive therapeutic intervention for dementia.