What you carry at this position in your DNA and what research says about it.
Alzheimer's Disease Risk: 8/10 evidence, 27 publications.
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Sample genotype (not yours): C/C
Typical Alzheimer's Disease Risk
Baseline genetic risk characterizes this profile for late-onset Alzheimer's disease. Microglia in the brain express typical levels of full-length CD33 protein, which regulates plaque clearance at a standard rate.
What this genotype means: Standard microglial plaque clearance rates; Baseline susceptibility to late-onset Alzheimer's; Slightly higher typical platelet and white blood cell counts.
Sample genotype (not yours): A/A
Slightly Lower Alzheimer's Disease Risk
Double copies of the protective A allele are linked to a slight reduction in the risk of developing late-onset Alzheimer's disease. This genotype promotes alternative splicing that helps microglia clear toxic brain plaques.
What this genotype means: Optimized microglial clearance of amyloid-beta plaques; Approximately 10% lower risk of late-onset Alzheimer's disease; Slightly lower baseline HbA1c and C-reactive protein levels.
Sample genotype (not yours): C/A
Possessing one copy of the protective A allele is linked to a slight reduction in the risk of developing late-onset Alzheimer's disease. This genetic variation helps the brain's immune cells clear toxic plaque build-ups more efficiently.
What this genotype means: Enhanced microglial clearance of amyloid-beta plaques; Approximately 10% lower risk of late-onset Alzheimer's disease; Slightly lower baseline C-reactive protein levels.
Gene function and biological role
Gene Function: The CD33 gene encodes a transmembrane receptor protein, also known as Siglec-3, which is primarily expressed on immune cells like microglia in the brain [1]. It acts as an inhibitory receptor that regulates innate immune responses and inflammatory signaling [2]. In the brain, CD33 plays a critical role in controlling how microglia clear cellular debris, including amyloid-beta plaques [3]. Higher levels of full-length CD33 protein on the surface of microglia suppress their ability to engulf and degrade these toxic protein aggregates [3]. Consequently, genetic variations that alter CD33 expression or structure are major determinants of susceptibility to neurodegenerative conditions [4].
Variant Impact: The rs3865444 variant is located in the promoter region of the CD33 gene and serves as a strong genetic marker for CD33 splicing efficiency [5]. The major C allele is associated with increased expression of the full-length CD33 protein on immune cells [6]. In contrast, the minor A allele promotes alternative splicing that skips exon 2, producing a shorter CD33 isoform that lacks the sialic acid-binding domain [5]. This shorter isoform is unable to inhibit microglial activity, allowing these brain immune cells to clear amyloid-beta plaques more effectively [3]. This single-nucleotide change thereby directly influences neuroinflammation and the accumulation of Alzheimer's-related pathology [1].
Key Insight: The protective A allele of this variant causes the brain's immune cells to skip a specific section of the CD33 protein, which prevents the protein from blocking plaque clearance. This natural genetic shield helps microglia keep the brain clean of toxic amyloid-beta build-ups.
Location: CD33. Chromosome 19 · 19q13.41 · 51.2 Mb
Estimated prevalence by population
Global 57.0%; European 46.8%; African 83.4%; East Asian 66.0%; South Asian 71.1%; Americas 32.7%; Ashkenazi 62.8%; Finnish 41.1%; Middle Eastern 55.2%; Amish 68.4%.
Estimated CC genotype frequency.
Global 35.1%; European 43.2%; African 15.9%; East Asian 30.5%; South Asian 26.4%; Americas 49.0%; Ashkenazi 32.9%; Finnish 46.0%; Middle Eastern 38.2%; Amish 28.6%.
Estimated CA 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 6.6%; Amish 3.0%.
Estimated AA genotype frequency.
Showing effects for C/C genotype
Neurology & Mental Health
Neurodegenerative Diseases
Alzheimer's Disease. Evidence: 8/10. Source: PMID 21460841. Typical Risk.
Cardiovascular & Metabolic
Blood Cell & Iron Traits
Platelet Count. Evidence: 9/10. Source: PMID 27863252. Slightly Higher.
Red Cell Distribution Width. Evidence: 8/10. Source: PMID 32888493. Slightly Higher.
White Blood Cell Count. Evidence: 8/10. Source: PMID 27863252. Slightly Higher.
Diabetes & Glycemic Traits
HbA1c. Evidence: 7/10. Source: PMID 39024449. Slightly Higher.
Immunity & Inflammation
Inflammatory & Circulating Protein Markers
C-Reactive Protein. Evidence: 8/10. Source: PMID 31900758. Slightly Higher.
Showing effects for A/A genotype
Alzheimer's Disease. Evidence: 8/10. Source: PMID 21460841. ~10% Lower Risk.
Platelet Count. Evidence: 9/10. Source: PMID 27863252. Slightly Lower.
Red Cell Distribution Width. Evidence: 8/10. Source: PMID 32888493. Slightly Lower.
White Blood Cell Count. Evidence: 8/10. Source: PMID 27863252. Slightly Lower.
HbA1c. Evidence: 7/10. Source: PMID 39024449. Slightly Lower.
C-Reactive Protein. Evidence: 8/10. Source: PMID 31900758. Slightly Lower.
Showing effects for C/A genotype
Platelet Count. Evidence: 9/10. Source: PMID 27863252. Typical.
Red Cell Distribution Width. Evidence: 8/10. Source: PMID 32888493. Typical.
White Blood Cell Count. Evidence: 8/10. Source: PMID 27863252. Typical.
HbA1c. Evidence: 7/10. Source: PMID 39024449. Typical.
C-Reactive Protein. Evidence: 8/10. Source: PMID 31900758. Typical.
What this genotype means for the people who carry it
Sample genotype: CC (Homozygous)
Inheriting two copies of the C allele is the most common genetic profile globally, representing the standard baseline for CD33 expression [1]. In this genotype, the CD33 gene undergoes typical splicing, resulting in standard levels of the full-length CD33 protein on the surface of microglia [2]. These brain immune cells use the full-length receptor to regulate their activity, which includes a standard rate of clearing amyloid-beta plaques [3]. Large-scale genome-wide association studies confirm that this genotype is associated with typical susceptibility to late-onset Alzheimer's disease [4]. It does not provide the protective, plaque-clearing advantage seen in carriers of the minor A allele [5]. Additionally, this genotype is associated with slightly higher baseline levels of platelets and white blood cells [6].
Standard microglial plaque clearance rates; Baseline susceptibility to late-onset Alzheimer's; Slightly higher typical platelet and white blood cell counts.
Sample genotype: AA (Homozygous)
Two copies of the protective A allele lead to the highest rate of alternative splicing for the CD33 gene, significantly reducing full-length CD33 protein levels on microglia [1]. Without the inhibitory signal of the full-length receptor, microglia are highly efficient at clearing amyloid-beta plaques from the brain [2]. Clinical and genetic studies show that this genotype provides a consistent, modest reduction in the risk of late-onset Alzheimer's disease [3]. This protective mechanism is a major focus of therapeutic research aiming to mimic this genetic shield to treat neurodegenerative diseases [4]. Beyond brain health, this genotype is linked to slightly lower baseline levels of C-reactive protein and blood sugar markers like HbA1c [5]. It also correlates with slightly lower typical counts of platelets and white blood cells [6].
Optimized microglial clearance of amyloid-beta plaques; Approximately 10% lower risk of late-onset Alzheimer's disease; Slightly lower baseline HbA1c and C-reactive protein levels.
Sample genotype: CA (Heterozygous)
A single copy of the protective A allele alters the splicing of the CD33 gene, reducing the amount of full-length CD33 protein on microglia [1]. This reduction in full-length CD33 prevents the protein from inhibiting microglial activity, allowing these immune cells to engulf and clear amyloid-beta plaques more effectively [2]. Multiple large-scale genetic studies have demonstrated that this genotype is associated with an approximate 10% reduction in the risk of late-onset Alzheimer's disease [3]. The protective effect has been observed across diverse populations, highlighting its broad biological significance [4]. In addition to its neuroprotective role, this genetic profile is associated with slightly lower baseline levels of inflammatory markers like C-reactive protein [5]. It also correlates with minor, typical variations in blood cell counts, including slightly lower platelets [6].
Enhanced microglial clearance of amyloid-beta plaques; Approximately 10% lower risk of late-onset Alzheimer's disease; Slightly lower baseline C-reactive protein levels.
Variants with shared genetic architecture
rs12459419 · CD33 Gene · Chr 19 · Alzheimer's Disease Risk
rs3826656 · CD33 Gene · Chr 19 · Alzheimer Disease Risk
rs11218343 · SORL1 Gene · Chr 11 · Alzheimer's Risk
CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology.
Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta.
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
CD33 Alzheimer's risk-altering polymorphism, CD33 expression, and exon 2 splicing.
The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease.
Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
Content updated August 2026.
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