ACTIVE MIND: An adaptive clinical trial of cognitive training to improve function and delay dementia

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PROJECT SUMMARY Dementia such as Alzheimer's disease (ADRD) is the most expensive medical condition20 in the US and affects more than 5 million Americans21. Analyses from the ACTIVE study showed that a specific type of computerized cognitive training (CTa) reduced risk of ADRD among older adults 29% across 10 years22. [Recent follow-up analyses indicate that ACTIVE participants with signs of mild cognitive impairment (MCI) at baseline randomized to CTa were 23% less likely to be diagnosed with ADRD across 20 years23]. While these results are encouraging, MCI was not clinically diagnosed and thus evidence is inconclusive to recommend CT for ADRD prevention. Many efficacious CT techniques now exist but have distinct cognitive effects. Given that cognitive deficits are varied among those with mild cognitive impairment (MCI), who are at higher risk for ADRD, a combination of CT techniques may be most efficacious. Significant knowledge gaps remain as the best CT exercise(s) for those with MCI is unclear. We were awarded a clinical trial planning grant to design and establish the feasibility of the ACTIVE MIND trial (AG062368). We propose phase II of ACTIVE MIND, an adaptive random- ized trial to identify the most efficacious CT exercises to improve everyday function in MCI. We will further quantify the effect size of CT to reduce incident ADRD among persons with MCI. In this phase II trial, our primary objective is to determine which CT arm results in the largest functional improve- ments and has the best probability to reduce ADRD incidence. Our investigators include international experts in CT, MCI/ADRD, recruitment and retention, neuropsychological assessment, neuroimaging, biomarkers, and adaptive trial design. Our approach is to compare different CT arms to a stringent active control condition with equivalent participant expectations. Measures will include innovative indi- ces of instrumental activities of daily living (IADL), standard cognitive assessments, as well as neu- roimaging and novel blood-based biomarkers. Potential moderators of CT will be assessed to identify who benefits. This study is innovative, in the application of adaptive trial methodology to efficiently identify the most efficacious CT exercises to reduce ADRD incidence in MCI. We further explore neu- roimaging and blood-based biomarkers as potential moderators of CT outcomes. Our premise is that targeted CT improves everyday function (i.e., IADL), which subsequently delays ADRD onset. Our long term goal is to improve older adults' functional trajectories and thereby curb ADRD prevalence. The contributions will be significant, advancing our understanding of how CT may be successfully im- plemented to curb ADRD prevalence. Significance is considerable given that an intervention delaying the onset of Alzheimer's disease by only one year will result in 9.2 million fewer cases of the disease by 205024.