Non-Invasive Home Neurostimulation for Mild to Moderate Alzheimer's Disease: Double-Blind, Sham Controlled Randomized Clinical Trial

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Abstract The growing prevalence of Alzheimer’s Disease coupled with a dearth of effective treatment options necessitates the development of novel treatment approaches for Alzheimer’s Disease, particularly those that pose minimal risk of adverse effects in a medically fragile population. Minimal risk, non- invasive neuromodulatory therapies, such as transcranial direct current stimulation (tDCS), may relieve symptoms and enhance function in older adults with diverse conditions. We developed an at home tDCS and demonstrated the feasibility of this approach, and in a pilot study conducted in patients with early Alzheimer’s disease, at home tDCS improved cognitive performance as well as stability in brain metabolism. We now propose to build and expand on the pilot study to test the clinical efficacy of home based tDCS using a rigorous double blind randomized clinical trial design in 100 patients with mild to moderate Alzheimer’s disease who will be randomized to receive either tDCS five days per week for six months at home or to sham treatment at the same frequency. All participants will receive cognitive assessments at baseline, post-intervention, and at one month and three months after intervention to explore and document durability of effects. Our primary outcome is change in cognitive performance (assessed by the Alzheimer's Disease Assessment Scale - Cognitive subscale test). Secondary outcomes include measures of mood, quality of life, and patient satisfaction with both the device and procedure. Neuroimaging markers of potential neuroplasticity will also be evaluated at baseline, post-intervention, and at three months post-intervention. We predict that the active tDCS will result in better cognitive performance, and higher quality of life, as compared to sham, and will be a satisfactory treatment approach for patients and their families. We also hypothesize that the clinical response produced by active tDCS will be associated with improved functional and structural connectivity and use of the Dorsolateral Prefrontal Cortex and associated networks (e.g. executive control/salience networks). The proposed study is highly responsive to PAR-19-298, which solicits applications to establish initial efficacy of neurostimulation/neuromodulation in the treatment of Alzheimer’s disease and related dementia. Our proposed clinical trial will provide high-quality evidence about the efficacy of at-home tDCS in the treatment of Alzheimer’s Disease. If efficacy is demonstrated, this non-invasive, non- pharmacologic intervention may become an important part of dementia care.