Alzheimer's disease (AD) will likely become the greatest public health crisis in the United States within the next 2-3 decades if left unchecked. There are no proven treatments that delay the onset or prevent the progression of AD, although a few promising candidates are under development. Even the earliest clinical symptoms of AD are accompanied by, and likely due to, neuronal/synaptic dysfunction and/or cell death. Thus, it is critical to identify individuals with "preclinical AD", prior to the development of clinical symptoms and concomitant neuronal loss, so new therapies will have the greatest clinical impact. At present, there are no antecedent biomarkers that will identify individuals with preclinical AD, however ongoing investigations of "at risk" populations, including those with Mild Cognitive Impairment (MCI), presymptomatic individuals harboring known disease-causing familial AD mutations or carriers of the epsilon4 allele of apolipoprotein E are offering insights into possible biomarkers of early disease processes. To discover antecedent biomarkers of AD, a prospective, longitudinal study of middle-aged individuals with positive or negative family history of AD has been initiated at Washington University in St. Louis. The Adult Children Study provides an opportunity to discuss the challenges and goals for investigations of antecedent AD biomarkers.