Considering the demographics of the population, we anticipate a profound increase in the prevalence of ageassociated disorders, none of which is more dreaded than AD. For the population over the age of 65, epidemiological and genetic linkage studies have uncovered important risk factors for AD. Examples of these phenotypic modifier alleles include apolipoprotein E4 (Apo E–ε4) and a polymorphic α2-macroglobulin (A2M-2) variant; additional genetic risk factors undoubtedly exist. For several years, Rudolph Tanzi and colleagues at Harvard Medical School have employed powerful family-based association studies and statistical approaches to identify genetic risk factors (A2M-2 among them) in the aging population. In his Perspective in this issue of the JCI, Tanzi offers a novel genetic dichotomy model based on the concept that while rare autosomal dominant inheritance of gene mutations causes highly penetrant early-onset form of the disease, the more common forms of AD that occur with advanced age are associated with the genetic risk factors that are distributed throughout the genome in the form of common population polymorphisms (CPPs). The ultimate goal of these studies is to assemble a genotypic profile for each individual that would determine the relative risk of acquiring AD, information that would be critical for making informed decisions regarding the use of potential therapeutic agents and clinical management.