rs6656401 — CR1 CR1 complement receptor Alzheimer's variant

Intronic variant in the complement receptor 1 gene; the minor A allele increases late-onset Alzheimer's disease risk with an odds ratio of ~1.21

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CR1 — When the Brain's Waste-Clearance Crew Falls Short

Complement receptor 1 (CR1, also known as CD35) is a molecular garbage collector. It sits on the surface of red blood cells, monocytes, and dendritic cells, binding to complement-tagged debris — including amyloid-beta oligomers11 amyloid-beta oligomers
the toxic protein fragments that accumulate in Alzheimer's disease — and shuttling them to the liver and spleen for destruction. The rs6656401 variant in the CR1 gene was identified in 2009 as one of the first genome-wide significant Alzheimer's risk loci beyond APOE, and it remains among the most robustly replicated genetic risk factors for late-onset disease.

The Mechanism

CR1 mediates immune adherence22 immune adherence
the process by which complement-opsonized particles are bound to erythrocytes and carried out of circulation. When complement proteins C3b or C4b coat amyloid-beta aggregates in the bloodstream or cerebrospinal fluid, CR1 on circulating red blood cells acts as a capture receptor, escorting the tagged debris to the reticuloendothelial system. The CLU gene (clusterin), identified in the same 2009 paper, performs a complementary amyloid-chaperoning role — lending biological plausibility to both genes as amyloid-clearance machinery.

A 2023 study measuring plasma protein levels showed that the A allele is significantly associated with increased soluble CR1 (sCR1) concentrations.

The Evidence

Lambert et al. (2009) in Nature Genetics33 Lambert et al. (2009) in Nature Genetics
first GWAS to identify CR1 as an AD risk locus beyond APOE reported an odds ratio of 1.21 (95% CI 1.14–1.29, P=3.7×10⁻⁹) for the rs6656401 A allele in a combined European dataset of over 9,000 individuals. The association was validated across five independent European cohorts, establishing CR1 as a genuine LOAD susceptibility locus.

A 2015 meta-analysis of 85,939 samples (30,100 cases; 55,839 controls) across 24 studies44 A 2015 meta-analysis of 85,939 samples (30,100 cases; 55,839 controls) across 24 studies
the largest pooled analysis specifically of rs6656401 confirmed the association with OR=1.18 (95% CI 1.15–1.22, P=1.82×10⁻²⁶) in combined populations, and OR=1.31 in East Asian samples — a finding that highlights population-specific effect sizes likely driven by differences in genetic background and LD patterns.

Liu et al. (2021), synthesizing 30 studies with over 68,000 participants55 Liu et al. (2021), synthesizing 30 studies with over 68,000 participants
the most comprehensive systematic review of CR1 variants in LOAD, confirmed OR=1.23 (95% CI 1.10–1.36) overall and OR=1.26 in European populations specifically, with the A allele as the risk allele in all models tested. The evidence level is strong: the association has been independently replicated across populations and study designs, and a plausible biological mechanism has been characterised. Clinical-guideline-level evidence (CPIC/DPWG) does not yet exist for CR1 because there are no genotype-specific approved interventions.

Practical Implications

Unlike pharmacogenomic variants with direct drug-dose consequences, the CR1 rs6656401 variant informs risk stratification and motivates a specific biological target: complement-mediated amyloid clearance. For A-allele carriers, the actionable focus is on supporting the complement and immune pathways that handle amyloid burden, and on early monitoring.

What is clear is that the A allele shifts complement biology in a direction associated with impaired amyloid clearance and increased disease risk.

The most actionable steps for A-allele carriers center on: (1) monitoring cognitive function early to catch any changes before they become irreversible, (2) managing the modifiable complement- and inflammation-activating factors (metabolic health, sleep quality, cardiovascular fitness) that amplify amyloid accumulation, and (3) awareness that participation in prevention trials is particularly valuable given the established, replicated risk.

Interactions

The most important interaction is with APOE genotype (rs429358 + rs7412). APOE ε4 affects amyloid-beta production and aggregation via lipoprotein pathways, while CR1 affects its clearance via complement. Carrying both CR1 risk alleles and APOE ε4 may represent compounding impairment of two independent amyloid-handling systems — accumulation plus impaired removal.

BIN1 rs744373 and CLU rs11136000 also influence amyloid and tau biology through different mechanisms. While no single study has formally quantified the combined effect of all four loci, polygenic risk scores incorporating CR1, BIN1, CLU, and APOE together predict Alzheimer's risk substantially better than any single variant alone, supporting the additive model that guides action in high-risk carriers.

Genotype Interpretations

What each possible genotype means for this variant.

GG Low-Risk Genotype Normal

Non-risk genotype; complement-mediated amyloid clearance unaffected by this variant

You carry two copies of the G allele at rs6656401, which is the common protective genotype. Approximately 77% of people carry this genotype globally. Your CR1-mediated complement clearance is not impaired by this variant. Alzheimer's disease risk from this locus is at population baseline; other genetic factors (particularly APOE status) and lifestyle variables will be the main determinants of your dementia risk.

AG Heterozygous Risk Carrier Intermediate

One copy of the CR1 risk allele; modestly increased Alzheimer's risk

You carry one copy of the A risk allele at rs6656401, a genotype found in roughly 21% of the population. This confers approximately 21% increased odds of developing late-onset Alzheimer's disease compared to the GG genotype (OR ~1.21 from the original GWAS; OR ~1.18 from the 85,939-sample meta-analysis). The effect operates through a complement-biology mechanism — the A allele is associated with increased soluble CR1 levels. The absolute lifetime risk increase from a single A allele is modest; this genotype is best considered alongside APOE status and other risk factors.

AA Homozygous Risk Carrier High Risk

Two copies of the CR1 risk allele; meaningfully elevated Alzheimer's risk

You carry two copies of the A risk allele at rs6656401, a genotype found in approximately 1.5% of the population. Homozygous carriers have the highest CR1-associated Alzheimer's risk from this locus — the additive model predicts roughly 45–50% increased odds relative to GG carriers (two risk copies × ~1.21 per copy in the additive model). Plasma soluble CR1 levels are significantly elevated in A-allele carriers. This genotype is clinically meaningful particularly when combined with APOE ε4 status and other Alzheimer's risk factors.