Transferrin (Tf), an iron-transporting protein, has many variants, but C1 and C2 variants account for the majority of the population in all races. Since Tf is reported to be immunocytochemically detectable in senile plaques in Alzheimer's disease (AD), we have examined the Tf allele frequency among AD patients. The C2 allele frequency in late-onset AD patients is significantly higher than that in age-matched controls. Unexpectedly, the C2 allele frequency in AD patients homozygous for the ApoE epsilon 4 allele is markedly increased, i.e., it is twice as high as that in the remaining AD patients carrying zero or one copy of the epsilon 4 allele.