Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia

The CD33 single-nucleotide polymorphism (SNP) rs3865444 has been associated with the risk of Alzheimer's disease (AD). Rs3865444 is in linkage disequilibrium with rs12459419 which has been associated with efficacy of an acute myeloid leukemia (AML) chemotherapeutic agent based on a CD33 antibody.We seek to evaluate the extent towhich CD33 genetics inADandAMLcan inform one another and advance human disease therapy.We have previously shown that these SNPs are associated with skipping of CD33 exon 2 in brain mRNA.Here,we report that these CD33 SNPs are associated with exon 2 skipping in leukocytes fromAMLpatients and with a novel CD33 splice variant that retains CD33 intron 1. Each copy of the minor rs12459419Tallele decreases prototypic full-length CD33 expression by ~25% and decreases the AD odds ratio by ~0.10. These results suggest that CD33 antagonists may be useful in reducingADrisk. CD33 inhibitorsmay include humanized CD33 antibodies such as lintuzumabwhichwas safe but ineffective inAML clinical trials. Here, we report that lintuzumab downregulates cell-surface CD33 by 80% in phorbol-ester differentiated U937 cells, at concentrations as lowas 10 ng/ml. Overall, we propose amodel wherein a modest effect on RNA splicing is sufficient tomediate the CD33 association with AD risk and suggest the potential for an anti-CD33 antibody as an AD-relevant pharmacologic agent.