ABSTRACT Despite the best scientific efforts, no new treatment for Alzheimer’s Disease (AD) has been approved by the FDA since 2003. However, this may not be due to the treatment under investigation but rather clinical heterogeneity within the study sample, as a subset of participants may not have AD or experience little to no decline in AD symptoms. Thus, to improve the likelihood of success, AD clinical trials must homogenize or enrich their study sample with individuals who will experience more rapid decline and are biologically- confirmed with AD. One enrichment solution is related to the degree of performance change a person experiences due to repeated exposure of a screening assessment, known as a practice effect. Practice effects can be used to inform prognosis, diagnosis and treatment response in AD. We have recently designed an online video game, called SuperG, that uses finger coordination to assess individual practice effects without supervision in less than 7 minutes. We intend to deploy our online video game into MindCrowd, an electronic cohort of >100,000 participants worldwide designed with the infrastructure for remote, large-scale, and widely- distributed research to discover and study early biomarkers of AD. The long-term goal of this project is to merge the PI’s experience in learning and video game development with his interest in AD-focused research to enhance his career in creating next-generation, ‘crowd-sourced’ screening procedures to enrich the AD clinical trial enterprise. The overall objective of this application is to utilize the MindCrowd electronic cohort to determine how learning capacity, assayed with SuperG, relates to changes in cognition and daily function over time, while providing valuable mentorship for the PI in motor-cognitive interactions, electronic cohorts and practice effects in the context of aging. Based on extensive published and pilot work from the mentorship team, the central hypothesis is that practice effects on SuperG will predict one-year changes in cognition and daily function among MindCrowd older adults. Since SuperG game play is easily collected online, the rationale for this proposed research in a distributed electronic cohort offers an affordable and efficient means to enrich clinical trials in AD. There are two independent aims within this proposal. First, we will determine the extent that SuperG practice effects predict one-year cognitive change in older adults. Second, we will determine the extent that SuperG practice effects predict one-year functional change in older adults. If successful, this project will provide cognitive aging research with a novel online screening tool that has the potential to enrich future Alzheimer’s Disease and Related Dementia clinical trials. This project also incorporates the PI’s career goals and training activities concerning: motor-cognitive interactions, electronic cohorts, and practice effects, together providing for independence in the establishment of a “virtual” lab with modern capabilities. Further, the ‘socially-distanced’ nature of this project is particularly relevant in the context of COVID-19 and will allow for the safe inclusion of participants remotely.

PROJECT NARRATIVE The proposed research is relevant to public health because of a growing need to innovate the current Alzheimer’s Disease (AD) clinical trial recruitment and assessment process in order to enhance trial efficacy. We propose the application of an online video game as a potential enrichment tool to predict long-term declines in older adult cognition and daily function relevant to AD, thereby aligning with new initiatives in NIA to identify key behavioral patterns/signals that are sensitive and specific to AD. The online nature of this proposed research allows for a fast, affordable and engaging enrichment technique that is particularly timely in the context of COVID-19, where participants can participate remotely in their homes without physical face-to-face contact.