An association between the epsilon 4 allele of the apolipoprotein E gene (APOE) and late-onset Alzheimer's disease (AD) was recently demonstrated. In order to confirm the association and to gauge the ability of standard genetic linkage methods to identify susceptibility genes, we investigated 15 Swedish late-onset Ad families. We found an association of familial AD to the APOE epsilon 4 allele (P = 0.01) but no indication of linkage to the APOE region using 2-point linkage analysis, and only weak evidence using the affected pedigree-member (APM) method. Our results confirm an APOE epsilon 4 association with late-onset familial AD and indicate that susceptibility genes can easily be missed when using standard lod score and APM genetic linkage analysis.