PROJECT SUMMARY/ABSTRACT Dementia cases due to Alzheimer's disease (AD) and related dementias are on the rise, and in the absence of a cure, the devastating impact has led to increased calls for expanded research. Behavioral interventions, such as exercise, have been noted to enhance brain health and can be useful in the prevention and remediation of cognitive decline, as in mild cognitive impairment (MCI). Our initial randomized controlled trial (RCT) investigated exergaming (Anderson-Hanley et al., 2012a), revealed significant cognitive benefit after three months of pedaling a virtual reality enhanced bike or “cybercycle,” compared with traditional pedaling only. Results suggest that for the same effort, interactive physical and mental exercise on a cybercycle can yield greater cognitive benefit than physical exercise alone on a stationary bike. Furthermore, there was a 23% reduction in risk of conversion to MCI among the cybercyclists. In a follow-up NIA-funded RCT, the Aerobic and Cognitive Exercise Study (ACES; Anderson-Hanley, 2018a), the PI and collaborators have worked to replicate and extend this line of research with patients with MCI. However, patients with MCI often declined to enroll citing travel to the location of the bike as a barrier. This sparked development of a portable, affordable tablet-based prototype: the interactive Physical and Cognitive Exercise System (iPACES) which can be paired with an under-table elliptical pedaler for in-home use. Data from in-home pilot trials (v1 & v2) by more than two dozen older adults pairs, found executive function significantly improved after 3-months of pedaling-to-play in the iPACES neuro-exergame, and more so than game-only (Anderson-Hanley et al., 2018b; Wall et al., 2018). The proposed research aims to: 1) enhance long-term exercise with iPACES via adding: a variety of interesting storyboards (e.g., tourist travel of states and countries), a virtual coach, smart watch notifications to promote adherence, and integration of tablet assessments with remote data capture, 2) pilot test the updated version of iPACES, 3) conduct an in-home multi-site clinical trial with 120 MCI-caregiver pairs comparing cognitive and biomarker outcomes from one-year of iPACES (pedal-to-play) with synchronous, but non-interactive physical and cognitive exercise (PACE; pedal-while-play), and 4) prepare results for publication and use in commercialization. Collaborators with wide-ranging expertise, will provide guidance in refining the games for long-term play, hardening the interface with equipment (e.g., iPad and smart-watch), and interfacing with reliable and valid unattended electronic assessment of cognition and behaviors. A randomized clinical trial will evaluate the cognitive and everyday impacts of six months of pedal-to-play iPACES, compared PACE-only, and use and effect after one year will also be assessed. Results will be prepared for publication and use in commercialization, as warranted, with the goal...