Different variants of the apolipoprotein E (APOE) gene have been associated with different levels of risk for developing Alzheimer’s disease. This long-term study will gather data in cognitively normal older adults and compare cognitive, behavioral, and physical changes across different APOE variants, or genotypes. We will develop, use, and extensively share critically important resources of cognitive, biomarker, genetic, and related data from cognitively unimpaired 50-90-year-old persons with each common form of APOE, the major Alzheimer’s disease susceptibility gene, representing six levels of risk. We will clarify the impact of APOE, other genetic and non-genetic factors, and their interactions on the predisposition to, protection from and potential prevention of Alzheimer’s disease, inform the design and size of 12 or 24-month prevention trials using biological outcome measurements, and demonstrate the value of extremely promising blood tests in these endeavors. We will provide an extensively shared resource of data, findings, biological samples, and motivated APOE-tested volunteers for the research community, support a wide range of other studies.