ADAS-Cog Trajectories Differ from Expected Decline in Dementia Following Repeated Non-Invasive Interventions over 3 Years

<i>Background and Objectives</i>: Non-pharmaceutical interventions such as cognitive training, transcranial electrical stimulation (tES), and repetitive transcranial magnetic stimulation (rTMS) have shown promise in improving cognitive outcomes in Alzheimer's disease (AD) and dementia. However, the long-term effects of repeated non-invasive interventions remain unknown. This study investigated whether repeated non-invasive interventions administered over a span of 1 to 3 years were associated with slower cognitive decline compared to typical AD progression, and whether longer no-treatment intervals between treatments predicted greater post-treatment decline. <i>Materials and Methods</i>: Seventy-three participants living with dementia or AD received 2 to 9 blocks of non-invasive treatments (including tES, rTMS, cognitive training). Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores were collected longitudinally up to 3 years (36 months), across multiple intervention and assessment sessions. A mixed-effects model was used to estimate the rate of cognitive decline, adjusting for baseline age, sex, and baseline cognition (MoCA) with participants being the random effect. The observed rate of change was compared to a meta-analysis estimate of AD progression. Additionally, a linear mixed-effects model using robust sandwich estimation of standard errors was employed to assess whether the no-treatment interval was associated with changes in ADAS-Cog scores. <i>Results</i>: Participants showed a significantly slower rate of cognitive decline than expected from the AD reference rate (<i>p</i> < 0.001), with many demonstrating stabilized ADAS-Cog scores during their respective treatment periods, ranging from 1 to 3 years. Medication analyses revealed no significant effect of AD medications, antidepressants, antihypertensives, or cholesterol-lowering agents on cognitive outcomes. Furthermore, longer no-treatment intervals were significantly associated with greater post-treatment decline (<i>p</i> < 0.001). <i>Conclusions</i>: Repeated non-invasive treatments seem to slow the rate of cognitive decline in individuals living with dementia when administered over a prolonged period. This study provides evidence supporting the feasibility and effects of personalized long-term non-invasive treatment strategies for dementia.