PROJECT ABSTRACT Advancing age is often accompanied by a decline of key neuromodulatory centers of the brain that support adaptive neuroplasticity. Deterioration of the underlying neurophysiology of the brain predisposes the individual to pathological and age-related cognitive decline. We propose to deploy a computerized cognitive training program (INHANCE) developed via two successful SBIR-funded phase II programs (R44AG039965; R44NS071780). The program will combine two previously validated, but historically independent, exercises that based on prior research may interact to reduce the long-term risk of dementia onset. We shall conduct a double-blind, parallel-arm, placebo-controlled, randomized clinical trial that will assess the short- and long-term efficacy of the program to improve neuromodulatory status (via positron-emission tomography) and neuropsychological outcomes (via standard assessment measures). The broader objectives of the project are two-fold. One is to address the rapid rise in neurodegenerative disease and the other is to shed light on the underlying neuromodulatory mechanism(s) through which certain forms of cognitive training achieve neuropsychological improvement. An effective, low-cost, and highly-scalable program available on the most popular internet-connected devices offers global reach and the possibility of extending the cognitive health of older adults. With effective computerized tools in hand we can enrich the lives of patients and their families, alleviate the enormous financial cost associated with minor and major forms of impairment, and progress swiftly toward the goal of creating a healthier society and a more efficient healthcare system.