ABSTRACT There is a pressing need for effective interventions to remediate age-related cognitive decline and alter the trajectory toward Alzheimer’s disease. The NIA Alzheimer’s Disease Initiative funded Phase III Augmenting Cognitive Training in Older Adults (ACT) trial aimed to demonstrate that transcranial direct current stimulation (tDCS) paired with cognitive training could achieve this goal. The present study proposes a state of the art secondary data analysis of ACT trial data that will further this aim by 1) elucidate mechanism of action underlying response to tDCS treatment with CT, 2) address heterogeneity of response in tDCS augmented CT by determining how individual variation in the dose of electrical current delivered to the brain interacts with individual brain anatomical characteristics; and 3) refine the intervention strategy of tDCS paired with CT by evaluating methods for precision delivery targeted dosing characteristics to facilitate tDCS augmented outcomes. tDCS intervention to date, including ACT, apply a fixed dosing approach whereby a single stimulation intensity (e.g., 2mA) and set of electrode positions on the scalp (e.g., F3/F4) is applied to all participants/patients. However, our recent work has demonstrated that age-related changes in neuroanatomy as well as individual variability in head/brain structures (e.g., skull thickness) significantly impacts the distribution and intensity of electrical current induced in the brain from tDCS. This project will use person-specific MRI-derived finite element computational models of electric current characteristics (current intensity and direction of current flow) and new methods for enhancing the precision and accuracy of derived models to precisely quantify the heterogeneity of current delivery in older adults. We will leverage these individualized precision models with state-of-the-art support vector machine learning methods to determine the relationship between current characteristics and treatment response to tDCS and CT. We will leverage the inherent heterogeneity of neuroanatomy and fixed current delivery to provide insight in the not only which dosing parameters were associated with treatment response, but also brain region specific information to facilitate targeted delivery of stimulation in future trials. Further still, the current study will also pioneer new methods for calculation of precision dosing parameters for tDCS delivery to potentially optimize treatment response, as well as identify clinical and demographic characteristics that are associated with response to tDCS and CT in older adults. Leveraging a robust and comprehensive behavioral and multimodal neuroimaging data set for ACT with advanced computational methods, the proposed study will provide critical information for mechanism, heterogeneity of treatment response and a pathway to refined precision dosing approaches for remediating age- related cognitive decline and altering the trajectory of older adults toward Alzheimer’s disease.

NARRATIVE This secondary data analysis leverages data from an Alzheimer’s Disease Initiative funded Phase III randomized clinical trial examining benefits of transcranial direct current stimulation paired with cognitive training to remediate age-related cognitive decline and alter trajectories toward Alzheimer’s disease. Using advanced neuroimaging-derived computational modeling and artificial intelligence-based machine learning methods, the study will determine the mechanisms underlying response vs. non-response to treatment in older adults and precision dosing parameters for optimizing treatment outcomes.