rs75932628 — TREM2 R47H

Rare missense variant in microglial receptor TREM2 that significantly increases late-onset Alzheimer's disease risk through impaired microglial function and amyloid clearance

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TREM2 R47H — A Rare but Potent Alzheimer's Risk Variant

TREM2 (Triggering Receptor Expressed on Myeloid cells 2) is a cell surface receptor found exclusively on microglia, the brain's resident immune cells. Microglia act as the brain's surveillance system11 Microglia act as the brain's surveillance system
monitoring for cellular debris, damaged neurons, and amyloid-beta aggregates, then clearing them through phagocytosis. The R47H variant, discovered in two landmark 2013 studies published simultaneously in the New England Journal of Medicine22 two landmark 2013 studies published simultaneously in the New England Journal of Medicine, represents one of the strongest genetic risk factors for late-onset Alzheimer's disease after APOE4.

This variant is exceptionally rare — about 0.25% of people carry one copy globally. Unlike common variants with modest effects, R47H has a dramatic impact: heterozygous carriers face approximately 3-fold increased AD risk33 heterozygous carriers face approximately 3-fold increased AD risk
recent meta-analysis across 26,847 cases confirmed OR 3.88, comparable to carrying one APOE4 allele.

The Mechanism — Impaired Microglial Surveillance

The R47H mutation changes arginine to histidine at position 47 in TREM2's extracellular ligand-binding domain.

The Evidence — From Discovery to Confirmation

The 2013 Guerreiro et al. study44 The 2013 Guerreiro et al. study
sequencing 1,092 AD patients and 1,107 controls, found 22 variant alleles in cases vs 5 in controls (P<0.001). The association has been consistently replicated across European populations55 consistently replicated across European populations
a 2015 meta-analysis of 24,086 cases and 148,993 controls confirmed OR 2.71 (P=4.67×10⁻²⁵).

Notably, the variant shows no significant association with AD in East Asian populations66 shows no significant association with AD in East Asian populations
likely due to its extreme rarity, with multiple Chinese studies finding zero R47H carriers. This population-specific effect emphasizes how rare variants can have different impacts depending on ancestry-specific allele frequencies and genetic backgrounds.

Practical Implications — Risk Assessment and Future Interventions

Carrying the R47H variant substantially elevates Alzheimer's risk, but penetrance is incomplete — not all carriers develop AD. The risk appears modulated by other genetic factors, particularly APOE77 risk appears modulated by other genetic factors, particularly APOE
some evidence suggests APOE4 may be required for AD to manifest in R47H carriers, though this remains controversial.

Currently, there are no specific interventions proven to reduce AD risk in R47H carriers.

Interactions — TREM2 and the Broader AD Landscape

TREM2 functions within a complex network of AD risk genes. The most important interaction is with APOE.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal TREM2 Function Normal

Standard microglial surveillance and amyloid clearance capacity

You have two copies of the common TREM2 variant, which encodes the normal R47 version of the receptor. About 99.5% of people of European descent share this genotype, and it's even more common in Asian and African populations. Your TREM2 receptors function normally, allowing microglia to effectively recognize damaged cells, amyloid deposits, and other signals requiring immune response in the brain.

CT R47H Carrier High Risk

Significantly elevated Alzheimer's disease risk through impaired microglial function

You carry one copy of the rare R47H variant, found in about 0.5% of Europeans and even rarer in other populations. This variant increases your risk of late-onset Alzheimer's disease approximately 3-fold compared to non-carriers — a risk magnitude similar to carrying one APOE4 allele. The mutation impairs TREM2's ability to bind its ligands, including amyloid-beta, phosphatidylserine, and apolipoprotein E, reducing microglial activation, migration to amyloid plaques, and phagocytic clearance. Not all carriers develop Alzheimer's — penetrance is incomplete and influenced by other genetic and environmental factors.

TT R47H Homozygous Homozygous

Extremely high Alzheimer's disease risk with dramatically earlier onset

You carry two copies of the R47H variant — an exceptionally rare genotype with only a handful of documented cases worldwide. Homozygous R47H carriers face increased risk of Alzheimer's disease compared to non-carriers. Your TREM2 function is severely impaired, dramatically reducing microglial ability to clear amyloid and respond to neuronal damage.