We have proposed an Alzheimer's Prevention Initiative (API) to relate a presymptomatic Alzheimer's disease (AD) treatment's biomarker effects to clinical outcome in cognitively normal people at the highest imminent risk to develop AD, including the world's largest kindred of early-onset AD (EOAD) causing mutation carriers (mean age at clinical onset=45), from Antioquia, Colombia. Here, we used longitudinal data from cognitively normal E280A Presenilin 1 (PS1) mutation carriers and non-carriers over age 35 to 1) characterize the combination of cognitive tests most sensitive to cognitive decline, 2) estimate the number of mutation carriers needed in randomized clinical trial (RCTs) to detect AD-slowing treatment effect on the composite cognitive endpoint, and 3) estimate the treatment effect that could be detected in 75 PS1 mutation carriers with 80% power and p=0.05. A battery of 19 cognitive tests, acquired every 2-5 years between 1995 and 2010 by the Neuroscience group at the University of Antioquia, was used to calculate the mean-to-standard-deviation ratios (MSDR) for each combination of one to six measurements. Measurements were adjusted for aging/practice effects using data from no carriers. The best combination was used to estimate statistical power in 24-60 month presymptomatic AD RCTs. After practice/aging correction, the optimal combination to predict cognitive decline included CERAD word list delayed recall, category verbal fluency, MMSE Orientation and Time, Constructional Praxis and Ravens progressive matrices. (A similar pattern was observed in cognitively normal older APOE4 carriers [Langbaum et al, ICAD abstract 2011]). We estimate the need for 215/79 PS1 mutation carriers per group over the age of 35, respectively, to detect a 25% treatment effect in a 24/60-month RCT. We estimate that 75 carriers per group would permit us to detect 43/26% treatment effects, respectively in a 24/60-month RCT. We have identified a combination of cognitive tests to evaluate presymptomatic AD treatments in cognitive normal people at highest imminent risk for EOAD. We have found a similar combination in those at highest risk for late-onset AD. We will continue to develop this approach in preparation for the presymptomatic AD/surrogate marker development trials proposed in the API.