The goal of the present randomized control trial is to evaluate the efficacy of a novel cognitive training approach using simulated games, where older adults will learn to flexibly deploy attentional control during working memory, for prevention of Alzheimer's Disease (AD). Based on our extensive pilot work, we expect training-related enhancements in both neural and cognitive functions on a broad range of cognitive abilities due to the importance of attentional control and working memory in many types of cognition. These outcomes are widely applicable to the cognitive health and the quality of life of elderly Americans, and have further potential to offset degenerative processes common to normal aging.

Almost all older adults experience cognitive frailty with age, with around one-third of adults aged 85 or older suffering from Alzheimer's disease (AD). Cognitive frailty, particularly AD, threatens to overwhelm medical resources in the United States and much of the developed world. Therefore, it is important that we learn how to optimize and maintain cognitive performance in cognitively-frail older adults, particularly those who are at high risk of suffering from AD, such as adults over 70 years of age where more than half express AD pathology. The present multi-arm randomized control trial takes a novel theory-driven approach to enhancing cognition in older adults by training them to flexibly deploy attentional focus in working memory. Flexibility in allocating and switching attentional resources will be trained by having participants respond to unpredictable cues in working memory. The ability to flexibly and efficiently allocate attentional control underlies successful performance on a broad array of cognitive tasks. Hence, training in this area may enhance performance not only on related tasks (near transfer) but also on tasks that are perceptibly not related to the training task (far transfer).

The current proposal has three training arms and utilizes game-based simulations in all arms in healthy older adults. The first two arms use experimenter-designed simulation games, where participants will be trained on either predictable low attentional control (Arm 1) or unpredictable high attentional control (Arm 2) working memory games. The third arm uses a commercially available strategy game requiring the highest level of attentional control, by adding multi-tasking to the unpredictable attentional shifts in working memory. In all three training arms, neural and cognitive changes in near (secondary outcome) and far (primary outcome) transfer tasks will be examined immediately after the intervention; cognitive changes will also be assessed at 6-month post-training duration. Additionally, a single-session, baseline neuroimaging data (no training) will be collected in a functional control group of younger adults. We expect that the high attentional control training arms will greatly improve both near and far cognition in older adults, with cognitive frailty interacting with the extent to which attentional control is trained. High attentional control training arms are also expected to heighten compensatory brain activation after the intervention, for both near and far in-scanner transfer tasks, mimicking the baseline activity of younger brains. These training arms are also expected to positively impact brain structures that progressively decline with aging. This clinical trial will result in the development of behavioral intervention tools, which will have the potential to delay the onset of memory-related disorders, such as AD, by instantiating durable improvements in cognitive functions in older adults. Such interventions can not only improve an individual's quality of life but also decrease the financial burden of a rapidly aging society.

Inclusion Criteria:

• At least a 10th grade education
• Learned English before age 5
• If female, not pregnant or likely to be pregnant
• Right-handed
• Mini Mental State (MMSE) score of 26 or greater (for older adults only), Montreal Cognitive Assessment (MoCA) score of 24 or more (for older adults only)
• The physical and sensory capacity sufficient to undertake a functional magnetic resonance imaging study

Exclusion Criteria:

• Color blindness assessed by the Ishihara Test for Color Deficiency
• Visual acuity of less than 20/30 on the Snellen eye chart after correction
• Diagnosis of any major psychiatric or neurologic disorders
• History of cardiovascular disease other than treated hypertension
• Illness or trauma affecting the central nervous system
• Substance/alcohol abuse, and medication with anti-depressants, anti-psychotics, or hypnotics other than occasionally at bedtime
• Structural magnetic resonance imaging reveal evidence of pathology (e.g. infarction)

If a volunteer meets the inclusion and exclusion criteria, he or she will be randomized into one of the three training arms. This assignment will be based on a random computerized allocation plan, where the average cognitive frailty, age, education and gender distribution will be maintained to be equivalent across the three arms. To maintain the balance between the arms, we will randomize between blocks of 15 participants. By randomly assigning participants in the training arms and by assessing outcomes by blinded experimenters, we will avoid selection bias and outcome assessment bias.

No masking is required for the younger adults, as they will not be undergoing any training.

The PI will be blinded to training assignment of any subject, and will only analyze de-identified data.