There is an urgent need to find demonstrably effective presymptomatic Alzheimer's disease (AD) treatments, those interventions intended to postpone the onset, reduce the risk of, or completely prevent AD symptoms. The Alzheimer's Prevention Initiative (API) aims to conduct presymptomatic AD treatment trials of amyloid-modifying treatments in cognitively normal people, who based on their age and genetic background, are at the highest imminent risk of AD symptoms; to relate a treatment's biomarker effects to clinical outcome; to provide a best test of the amyloid hypothesis; to give persons at highest risk access to promising investigational treatments; to provide exceptionally large Alzheimer's Prevention registries for these and other presymptomatic trials; and to complement, support and benefit from other initiatives. The API includes a) a planned presymptomatic AD treatment/biomarker development/nested cohort trial in cognitively normal early-onset AD-causing mutation carriers within 15 years of their estimated age at clinical onset, including PS1 E280A mutation carriers from the world's largest kindred in Antioquia, Colombia; b) a proposed presymptomatic AD treatment/biomarker development trial in cognitively normal APOE Îμ4 homozygotes and heterozygotes; c) an exceptionally large early-onset AD prevention registry in the PS1 E280A kindred; and d) development of an exceptionally large internet-based Alzheimer's Prevention Registry to support the entire research community. We continue to characterize the preclinical trajectory of early-onset and late-onset AD in our PS1 E280A and APOE cohorts, establish a composite cognitive endpoint with improved power to track evaluate presymptomatic AD treatments; estimated presymptomatic trial sample sizes using amyloid PET, FDG PET, MRI, CSF and cognitive endpoints, vet treatment options for these and other trials, engage a large number of academic, industry and regulatory stakeholders; launch our registries; and prepare for our first presymptomatic trial. We are excited about our progress, plans, current timelines and the chance to work with other researchers, programs, and stakeholders. Together, we have a chance to set the stage of a new era in AD prevention research, develop the resources, biomarker endpoints, and accelerated regulatory approval pathway needed to rapidly evaluate the range of promising presymptomatic treatments, and find ones that work as soon as possible.