Design and Rationale of the PACt-MD Randomized Clinical Trial: Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression

Background: By the time Alzheimer's disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. Results: PACt-MD (Prevention of Alzheimer's dementia with Cognitive remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) plus transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. The primary aims are to compare the efficacy of CR+ tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. The secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of several biomarkers collected from the participants. Conclusion: PACt-MD is unique in combining brain stimulation and a psychosocial intervention to prevent ADRD. PACtMD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD.