This ongoing trial (Phase 2) recruited participants who were either known to have a disease-causing mutation (presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP)) or who were at risk for such a mutation (the child or sibling of a proband with a known mutation) and unaware of their genetic status from the Dominantly Inherited Alzheimer’s Network (DIAN), a multicenter international longitudinal observational study supported by the National Institutes of Health (U01-AG032438). This talk will discuss the design and analytic challenges that have emerged from the trial, including multiple drugs with different mechanisms of action and a delayed treatment arm on the biomarker phase, multiple primary efficacy endpoints, multiple regions/sites, randomization and minimization across multiple regions, power analyses, interim and final efficacy analyses. This talk will also discuss the seamless transition to cognitive endpoint phase (Phase III), i.e., the anticipated design and analytic challenges including the selection and analyses of primary cognitive endpoint for the Phase III trial across regions.