Elucidating the mechanism whereby genetics impact the risk of Alzheimer’s disease (AD) is a critical barrier to progress in translating genetics to pharmacologic strategies. A polymorphism near CD33 has been identified as an AD risk factor in multiple genome wide association studies, including very recent, very large studies. CD33 is a member of the sialic acid-binding immunoglobulin-type lectin (SIGLEC) family which is linked to regulation of innate immunity. We and others have found that CD33 expression is restricted to microglia in the brain. Moreover, the AD-protective allele acts to increase a CD33 isoform lacking exon 2 (D2-CD33) at the expense of full-length CD33. Since exon 2 encodes the sialic acid ligand binding domain, we interpreted the finding that loss of exon 2 was associated with decreased AD risk as meaning that a decrease in functional CD33 and its associated immune suppression was AD-protective. However, this interpretation needs to be reconsidered given our recent finding that a 4 bp CD33 genetic deletion, which abrogates CD33, is not associated with AD risk. In summary, we currently propose a model wherein the D2-CD33 isoform represents a gain of function variant to reduce AD risk because (i) a genetic polymorphism that reduces AD risk increases D2-CD33 at the expense of “full-length” CD33 but (ii) a CD33 indel that essentially deletes cell surface CD33 does not affect AD risk. To test this model, we propose the following Specific Aims. Specific Aim 1: Evaluate whether changes in CD33-related gene expression may compensate for CD33 deficiency. Specific Aim 2: Determine D2-CD33 subcellular localization under conditions of physiologic D2-CD33 expression. Specific Aim 3: Compare CD33 and D2-CD33 interactomes. Specific Aim 4: Compare impact of CD33 and D2-CD33 on cellular functions critical to microglia. Successful completion of these studies will pinpoint D2-CD33 as the primary pharmacologic target in this locus to reduce AD risk.