OBJECTIVE: The familial aggregation of late-onset Alzheimer's disease (AD) might be caused by the clustering of genetic risk factors in families. This study investigates the influence of variants of candidate genes on the familial aggregation of AD. METHODS: The occurrence of AD was examined in 1,420 first-degree relatives of 70 AD patients and 144 nondemented controls classified by the presence of AD and relevant candidate genes in index subjects. RESULTS: Relatives of nondemented controls with an apolipoprotein E4 or a cathepsin D T allele had a higher cumulative lifetime incidence of AD than relatives of subjects without the respective alleles. This effect was not detected in relatives of AD patients. Variants of the interleukin-6, bleomycin hydrolase and alpha(2)-macroglobulin genes did not significantly influence the (age-adjusted) risk of AD in relatives. CONCLUSIONS: Familial aggregation of late-onset AD is likely to be caused by several genetic risk factors. Variants of the apolipoprotein E and cathepsin D genes influenced the risk of AD in relatives of nondemented control subjects. The lack of an influence of these genotypes on the risk of AD in relatives of AD subjects may be the consequence of complementary reductions of other genetic risk factors such as various, yet unknown susceptibility genes in patients and, consequently, in their first-degree relatives.