What you carry at this position in your DNA and what research says about it.
Alzheimer's Disease Risk: 10/10 evidence, 21 publications.
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Sample genotype (not yours): C/C
Typical Alzheimer's Risk and Standard Immune Response
Standard levels of full-length CD33 protein are maintained, resulting in typical baseline risk for late-onset Alzheimer's disease. If treated for acute myeloid leukemia, this genotype is associated with an excellent response to the targeted drug gemtuzumab ozogamicin.
What this genotype means: Typical baseline risk of late-onset Alzheimer's disease; Excellent clinical response to gemtuzumab ozogamicin therapy in AML.
Sample genotype (not yours): C/T
Lower Alzheimer's Risk
Carrying one copy of the protective variant alters CD33 splicing, which enhances the brain's ability to clear amyloid plaques. This leads to a lower baseline risk of late-onset Alzheimer's disease.
What this genotype means: Reduced baseline risk of late-onset Alzheimer's disease; Moderate response to gemtuzumab ozogamicin therapy in AML.
Sample genotype (not yours): T/T
Lowest Alzheimer's Risk
Carrying two copies of the protective variant significantly reduces full-length CD33 expression, promoting plaque clearance in the brain. This results in the lowest baseline risk of late-onset Alzheimer's disease.
What this genotype means: Lowest baseline risk of late-onset Alzheimer's disease; Poor clinical response to gemtuzumab ozogamicin therapy in AML.
Gene function and biological role
Gene Function: The CD33 gene encodes a transmembrane receptor expressed primarily on myeloid cells, including microglia in the brain [1]. It acts as an inhibitory receptor that dampens immune responses, particularly microglial phagocytosis [2]. In the context of Alzheimer's disease, CD33 activity regulates the clearance of amyloid-beta plaques [2]. High levels of full-length CD33 can suppress the brain's ability to clear these toxic protein deposits [2]. Conversely, reducing CD33 activity or expression has been shown to enhance plaque clearance [2].
Variant Impact: The rs12459419 variant is a missense change located in exon 2 of the CD33 gene that alters mRNA splicing [2]. The reference C allele produces full-length CD33, which contains the IgV domain required for ligand binding and immune suppression [2]. The variant T allele promotes skipping of exon 2, resulting in a truncated CD33 isoform that lacks this binding domain [2]. This alternative splicing reduces full-length CD33 expression on the cell surface [3]. Consequently, the variant alters both neuroinflammatory pathways and the binding of certain targeted cancer therapies [4].
Key Insight: A genetic variant that protects against Alzheimer's disease by helping the brain clear plaques also reduces the effectiveness of a major leukemia drug.
Location: CD33. Chromosome 19 · 19q13.41 · 51.2 Mb
Estimated prevalence by population
Global 57.0%; European 46.8%; African 83.3%; East Asian 65.9%; South Asian 71.1%; Americas 32.8%; Ashkenazi 62.7%; Finnish 41.0%; Middle Eastern 54.5%; Amish 68.4%.
Estimated CC genotype frequency.
Global 35.2%; European 43.2%; African 15.9%; East Asian 30.6%; South Asian 26.4%; Americas 48.9%; Ashkenazi 32.9%; Finnish 46.1%; Middle Eastern 38.7%; Amish 28.6%.
Estimated CT genotype frequency.
Global 7.8%; European 10.0%; African 0.8%; East Asian 3.5%; South Asian 2.4%; Americas 18.3%; Ashkenazi 4.3%; Finnish 12.9%; Middle Eastern 6.9%; Amish 3.0%.
Estimated TT genotype frequency.
Showing effects for C/C genotype
Neurology & Mental Health
Neurodegenerative Diseases
Alzheimer's Disease. Evidence: 3/10. Source: PMID 25762156. Typical Risk.
Pharmacogenomics
Chemotherapy Response
Leukemia Drug Response. Evidence: 3/10. Source: PMID 23444229. Excellent Response.
Immunity & Inflammation
Inflammatory & Circulating Protein Markers
CD33 Protein Levels. Evidence: 8/10. Source: PMID 28240269. Higher.
Cardiovascular & Metabolic
Blood Cell & Iron Traits
White Blood Cell Count. Evidence: 10/10. Source: PMID 32888494. Slightly Higher.
Showing effects for C/T genotype
Alzheimer's Disease. Evidence: 3/10. Source: PMID 25762156. Lower Risk.
Leukemia Drug Response. Evidence: 3/10. Source: PMID 23444229. Reduced Response.
CD33 Protein Levels. Evidence: 8/10. Source: PMID 28240269. Intermediate.
White Blood Cell Count. Evidence: 10/10. Source: PMID 32888494. Typical.
Showing effects for T/T genotype
Alzheimer's Disease. Evidence: 3/10. Source: PMID 25762156. Lowest Risk.
Leukemia Drug Response. Evidence: 3/10. Source: PMID 23444229. Poor Response.
CD33 Protein Levels. Evidence: 8/10. Source: PMID 28240269. Lower.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Maintaining two copies of the C allele ensures standard expression of full-length CD33 on microglia and other myeloid cells [1]. This typical expression level is associated with standard baseline risks for late-onset Alzheimer's disease [2]. Because the full-length protein contains the intact IgV domain, it serves as an ideal target for antibody-drug conjugates [3]. In patients diagnosed with acute myeloid leukemia, this genotype predicts an excellent clinical response to the targeted drug gemtuzumab ozogamicin [3]. Standard levels of white blood cells and neutrophils are also typically observed [4].
Typical baseline risk of late-onset Alzheimer's disease; Excellent clinical response to gemtuzumab ozogamicin therapy in AML.
Sample genotype: CT (Heterozygous)
Possessing one copy of the T allele leads to intermediate levels of alternative splicing, producing both full-length and truncated CD33 proteins [1]. The reduction in full-length CD33 on microglia decreases inhibitory signaling, which enhances the clearance of amyloid-beta plaques in the brain [2]. This functional change is linked to a lower risk of developing late-onset Alzheimer's disease [2]. However, the presence of the truncated isoform reduces the availability of the binding site for certain immunotherapies [3]. If treated for acute myeloid leukemia, this genotype is associated with a reduced clinical benefit from gemtuzumab ozogamicin [3].
Reduced baseline risk of late-onset Alzheimer's disease; Moderate response to gemtuzumab ozogamicin therapy in AML.
Sample genotype: TT (Homozygous)
Carrying two copies of the T allele significantly increases alternative splicing, resulting in a high proportion of the truncated CD33 isoform [1]. This dramatic reduction in full-length CD33 minimizes inhibitory signaling on microglia, allowing for highly efficient clearance of amyloid-beta plaques [2]. Clinical studies associate this genotype with the lowest baseline risk of late-onset Alzheimer's disease [2]. On the other hand, the lack of the IgV domain means that the target for certain antibody-drug conjugates is largely absent [3]. Consequently, patients with this genotype do not derive significant benefit from gemtuzumab ozogamicin therapy in acute myeloid leukemia [3].
Lowest baseline risk of late-onset Alzheimer's disease; Poor clinical response to gemtuzumab ozogamicin therapy in AML.
Variants with shared genetic architecture
rs3865444 · CD33 Gene · Chr 19 · Alzheimer's Disease Risk
rs3826656 · CD33 Gene · Chr 19 · Alzheimer Disease Risk
rs35349669 · INPP5D Gene · Chr 2 · Alzheimer Disease Risk
Genetics of CD33 in Alzheimer's disease and acute myeloid leukemia.
CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing.
Connecting genetic risk to disease end points through the human blood plasma proteome.
The Polygenic and Monogenic Basis of Blood Traits and Diseases.
Content updated August 2026.
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