Typical, later-onset forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci, combinations of which contribute to the development of this disorder. We previously reported the results of a systematic survey of the human genome for the identification of highly informative DNA polymorphisms (SSTRPs) that target new AD risk genes. In addition to the APOE locus, our survey detected five new candidate susceptibility loci for AD, including D10S1423. An association of the D10S1423 234-bp allele with AD has been reported in three independent samples of AD cases and controls (Boston, Pittsburgh, Bonn). Data from our case-control studies suggest a strong synergistic interaction between the D10S1423 234-bp and APOE E4 risk alleles (234-bp carrier: OR = 2.5, 95% CI = 1.4--4.5; E4 carrier: OR = 8.3, 95% CI = 4.3--15.8; both alleles: OR = 23.1, 95% CI = 5.3--99.5). This report describes the prospective, longitudinal, double-blind assessment of the age-specific risk of AD encountered by 325 asymptomatic first-degree relatives of AD probands who carried the D10S1423 234-bp allele, the APOE E4 allele, or both, after 11.5 years of systematic follow-up. A total of 18 incident cases of AD were detected during the first 3379 subject-years of this longitudinal study. The effects of carrying either or both of the D10S1423 234-bp and APOE E4 alleles on the age-specific risk of developing AD were determined using Kaplan-Meier survival analysis. The age-specific risk of developing AD was the greatest for individuals who carried both alleles (Mantel--Cox statistic = 20.12, df = 3, P = 0.0002; Breslow statistic = 13.36, df = 3, P = 0.004). Cox proportional hazards models were developed to estimate the risk ratios for each genotype, controlling for the potential effects of age at recruitment, sex, and years of education. In the resulting best fitting model, only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1 (risk ratio = 16.2, P = 0.008, 95% CI = 2.1--128.3). After controlling for these genotypes, female gender was also significantly associated with increased risk of developing AD (risk ratio = 5.1, P = 0.02, 95% CI = 1.2--21.1). Neither age at recruitment nor years of education made significant contributions to the model.