Typical forms of Alzheimer's disease (AD) appear to be influenced by multiple susceptibility loci. 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 (AD7) 234 bp allele, the APOE E4 allele, or both, after 14 years of systematic follow-up. A total of 30 incident cases of AD were detected during the first 3752 subject-years of surveillance. 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 risk of developing AD was the greatest for individuals who carried both alleles (Mantel-Cox statistic = 16.46, df = 3, P = 0.0009; Breslow statistic = 13.38, 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. Only individuals who carried both risk alleles exhibited a risk ratio that differed significantly from 1 (risk ratio = 7.5, P = 0.002, 95% CI = 2.1-27.0). Neither age at recruitment, sex, nor years of education made significant contributions to the model, although women tended to be at greater risk (P = 0.06). Recent evidence that D10S1423 resides within open reading frame C10orf112, whose predicted product resembles a low-density lipoprotein receptor, suggests a molecular mechanism for this gene-gene interaction.
(c) 2009 Wiley-Liss, Inc.