Six-month randomized, double-blind trial of transcranial direct current stimulation in mild Alzheimer's dementia: domain-specific cognitive and neuropsychiatric signals

Abstract

Background: Prefrontal transcranial direct current stimulation (tDCS) is a low-risk candidate intervention for cognitive enhancement in Alzheimer's disease (AD), but trial results are heterogeneous and often short-term. We evaluated the 26-week efficacy, safety, and family-level impact of home-based prefrontal tDCS in mild AD. Methods: In this randomized, double-blind, sham-controlled trial, 120 patients with mild AD were allocated to active (n = 59) or sham (n = 61) tDCS. The intention-to-treat (ITT) population included 106 participants (53 vs. 53) with post-baseline data; 66 (32 vs. 34) comprised the per-protocol (PP) set. The primary outcome was change in global cognition on the Korean Mini-Mental State Examination (K-MMSE). Secondary and exploratory outcomes included domain-specific cognition (e.g., Korean Boston Naming Test [K-BNT]), neuropsychiatric symptoms (Korean Neuropsychiatric Inventory [K-NPI]), patient quality of life (QoL-AD), and caregiver-reported family quality of life (Family Quality of Life– Dementia [FQoL-D]). Adverse events (AEs) were systematically monitored. Results: K-MMSE declined slightly in both groups over 26 weeks (active Δ −0.53, sham Δ −0.15), with no significant between-group difference (p = 0.402). Most cognitive domains showed small, nonsignificant changes. In contrast, confrontation naming on the K-BNT favored active tDCS: in ITT analyses, naming performance was stable with active stimulation (Δ +0.51) but worsened with sham (Δ −2.32; p = 0.022), with a similar pattern in the PP set. K-NPI findings were inconsistent across analytic 3 sets. Notably, FQoL-D declined in the active arm but improved in the sham arm in both ITT (Δ −2.19 vs. +1.94; p = 0.043) and PP analyses. Overall AE rates were similar; stimulation-site reactions were common but mild, and serious AEs were rare and deemed unrelated to tDCS. Conclusion: In mild AD, 26 weeks of home-based prefrontal tDCS did not improve global cognition versus sham, although a modest benefit in confrontation naming was observed. The deterioration in caregiver-reported family quality of life highlights the need to weigh potential cognitive gains against family burden in long-term home-based neuromodulation. Clinical trial registration: Clinical Research Information Service (CRIS), KCT0005834.