Combination therapy slows cognitive decline in depression and MCI

Cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) is effective in slowing cognitive decline in older adults with remitted major depressive disorder (MDD), mild cognitive impairment (MCI), or both, according to a randomized clinical trial.

“Older adults with MCI or MDD constitute two overlapping groups who are at high risk of cognitive decline and dementia … thus, interventions that could reduce the risk are needed,” wrote the researchers. “The goal [of the combination regimen] was to activate the prefrontal cortex with CR and tDCS to improve cognitive compensation and slow cognitive decline of normal ageing, which is accelerated in remitted MDD or MCI.” [JAMA Psychiatry 2025;82:12-21]

In the current randomized clinical trial, the researchers recruited older adults who had remitted MDD (with or without MCI, age ≥65 years) or MCI without remitted MDD (age ≥60 years) to assess the efficacy of CR plus tDCS in slowing cognitive decline. A total of 375 patients (mean age, 72.2 years; female, 62 percent) received either CR plus tDCS or sham plus sham 5 days a week for 8 weeks, followed by twice-a-year 5-day boosters and daily at-home CR or sham CR. The primary outcome was change in global composite cognitive score.

After a median follow-up of 48.3 months, CR and tDCS slowed cognitive decline vs sham plus sham for up to 6 years (adjusted z score difference at 60 months, 0.21; 95 percent confidence interval [CI], 0.07–0.35; likelihood ratio test [LRT] p=0.006).

The effect was even more pronounced in executive function (adjusted z score difference at 2 months, 0.15; 95 percent CI, 0.02–0.28; LRT p=0.04) and verbal memory (adjusted z score difference at 2 months, -0.02; 95 percent CI, -0.17 to 0.12; LRT p=0.02), with weaker evidence for other domains, such as language, visuospatial memory, processing speed, and working memory.

Preplanned analyses showed that the treatment effect was larger in patients with remitted MDD vs MCI without MDD (p=0.01) and in APOE ε4 noncarriers vs APOE ε4 carriers (p<0.001).

Previously, few trials examined the efficacy of CR plus tDCS in older patients with MCI, none lasted >12 weeks, sample sizes ranged between 67 and 201 patients, and all showed negative results. No trials examined the efficacy of CR plus tDCS in remitted MDD. [Alzheimers Dis 2019;71:503-512; Ann Clin Transl Neurol 2019;6:1938-1948; Ann Phys Rehabil Med 2021;64:101536; JAMA Psychiatry 2025;82:12-21]

“Our study showed that CR plus tDCS, both targeting the prefrontal cortex, is efficacious in slowing cognitive decline in at-risk older adults, particularly those with remitted MDD [with or without MCI] and those at low genetic risk of Alzheimer’s disease,” summarized the researchers.