Longitudinal Non-Pharmacological Neuromodulation and Cognitive Training Across Sequential Intervention Studies in a Participant with Alzheimer’s Disease: A 10-Year Single-Participant Analysis

Objectives: Non-pharmacological interventions for Alzheimer’s disease (AD) are typically studied as single modalities over months; long-term, multi-modal outcome data in one individual, of clear relevance to the psychiatric care of older adults with dementia over time, are rare. We describe the cognitive trajectory of one participant who, over 10 years, took part sequentially in five non-invasive AD intervention studies, and place his cognitive change in the context of decline rates reported in published AD cohorts. Methods: Retrospective, single-participant analysis integrating data from a university research laboratory (University of Manitoba, Canada; 2013–2025) across five sequential protocols: virtual-reality (VR) navigational neurorehabilitation; a randomized trial of repetitive transcranial magnetic stimulation (rTMS); cognitive training with/without 40 Hz transcranial alternating current stimulation (tACS); a crossover sham-controlled tACS study; and an ongoing personalized-frequency tACS/tDCS study. The participant was one male, healthy at 2013 enrollment, later diagnosed with mild cognitive impairment (2016) and AD (2018), who received no pharmacological AD treatment. Interventions included VR spatial navigation training; bilateral DLPFC rTMS; 40 Hz and personalized gamma/theta tACS/tDCS over left DLPFC paired with cognitive exercises; and intermittent cognitive-training-only blocks. Outcomes were assessed with the MoCA, ADAS-Cog, Neuropsychiatric Inventory Questionnaire, and VR navigation error. Long-term ADAS-Cog change was quantified with linear regression (slope, 95% CI) for the intervention and post-intervention periods, with sensitivity and segmented (interrupted time-series) analyses. Results: Over the ~5.4-year intervention period (November 2018–April 2024), which comprised 12 four-week intervention blocks separated by treatment-free intervals, ADAS-Cog fluctuated between 12.3 and 23.0 but showed no significant long-term trend (slope +0.32 points/year; 95% CI −0.25 to 0.89). Published group-level data suggest a decline of approximately 10–12 points over a comparable interval. ADAS-Cog was higher at the two latest assessments after treatment ended (22.0 and 22.3), but these values were within the range observed during intervention, and post-intervention data were too sparse to estimate a reliable trend. MoCA was 21 in 2018 and 2021, 19 in October 2022, and 13 in March 2025; when the latter decline occurred within that interval cannot be determined. Conclusions: In this single participant, a period of repeated, intermittent non-invasive brain stimulation combined with cognitive training was temporally associated with a flat long-term ADAS-Cog trajectory, slower than published group-level decline rates. Because the design is retrospective and uncontrolled, these observations cannot establish the efficacy of any intervention or attribute later changes to treatment cessation. They are hypothesis-generating, relevant to clinicians managing long-term cognitive care in dementia, and support controlled studies of long-term individualized non-invasive brain stimulation with cognitive training.