rs75932628 — TREM2 R47H

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
one from Iceland showing an odds ratio of 2.92, the other from multiple European cohorts with OR 4.5, 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, with slightly higher frequencies in Icelanders at 0.63% and Ashkenazi Jewish populations at 1.4%³³ Icelanders at 0.63% and Ashkenazi Jewish populations at 1.4%
while nearly absent in East Asian and African populations. Unlike common variants with modest effects, R47H has a dramatic impact: heterozygous carriers face approximately 3-fold increased AD risk⁴⁴ heterozygous carriers face approximately 3-fold increased AD risk
recent meta-analysis across 28,007 cases confirmed OR 3.88, comparable to carrying one APOE4 allele. Even more striking, the handful of identified homozygous R47H carriers show an odds ratio of 97.1 for Alzheimer's disease⁵⁵ the handful of identified homozygous R47H carriers show an odds ratio of 97.1 for Alzheimer's disease
with AD onset 6.4 years earlier than other patients.

The Mechanism — Impaired Microglial Surveillance

The R47H mutation changes arginine to histidine at position 47 in TREM2's extracellular ligand-binding domain, specifically within the complementarity-determining region that recognizes lipids, apolipoproteins, and amyloid-beta⁶⁶ specifically within the complementarity-determining region that recognizes lipids, apolipoproteins, and amyloid-beta
the mutation disrupts the receptor's ability to bind these ligands. This impaired binding has cascading consequences for microglial function.

Wild-type TREM2 binds to phosphatidylserine exposed on damaged neurons, apoptotic cells, and amyloid-beta aggregates⁷⁷ Wild-type TREM2 binds to phosphatidylserine exposed on damaged neurons, apoptotic cells, and amyloid-beta aggregates
triggering microglial activation, migration to sites of damage, and phagocytosis. The R47H variant shows reduced binding affinity to all these ligands, particularly to apolipoprotein E⁸⁸ reduced binding affinity to all these ligands, particularly to apolipoprotein E
the major lipid transporter in the brain. In mouse models and human brain tissue, R47H carriers show fewer microglia clustering around amyloid plaques⁹⁹ R47H carriers show fewer microglia clustering around amyloid plaques
and the plaques that form are more diffuse and toxic to surrounding neurons.

Recent studies suggest R47H may actually be a gain-of-function mutation in some contexts¹⁰¹⁰ gain-of-function mutation in some contexts
increasing phagocytosis of synapses and stressed-but-viable neurons, potentially contributing to neuronal loss. The variant also impairs microglial metabolic function, reducing oxidative phosphorylation and mitochondrial respiratory capacity¹¹¹¹ impairs microglial metabolic function, reducing oxidative phosphorylation and mitochondrial respiratory capacity
limiting the energy available for sustained phagocytosis and inflammatory responses.

The Evidence — From Discovery to Confirmation

The R47H variant was first linked to neurodegenerative disease through families with Nasu-Hakola disease¹²¹² first linked to neurodegenerative disease through families with Nasu-Hakola disease
where homozygous loss-of-function TREM2 mutations cause early-onset dementia with bone cysts. This led researchers to investigate whether heterozygous TREM2 variants might increase late-onset AD risk.

The 2013 Guerreiro et al. study¹³¹³ 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). Simultaneously, Jonsson et al. in Iceland¹⁴¹⁴ Jonsson et al. in Iceland
studying 3,550 AD patients and 8,888 elderly controls, identified R47H with OR 2.92 (P=3.42×10⁻¹⁰). The association has been consistently replicated across European populations¹⁵¹⁵ 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 populations¹⁶¹⁶ 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 APOE¹⁷¹⁷ 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. However, understanding the mechanism suggests potential strategies: therapies that enhance microglial function, improve amyloid clearance, or restore TREM2 signaling¹⁸¹⁸ therapies that enhance microglial function, improve amyloid clearance, or restore TREM2 signaling
could theoretically benefit R47H carriers. The development of anti-amyloid antibodies like lecanemab and donanemab¹⁹¹⁹ anti-amyloid antibodies like lecanemab and donanemab
which work by promoting microglial phagocytosis of amyloid, might be particularly relevant.

General Alzheimer's prevention strategies remain important: cardiovascular health, physical exercise, cognitive engagement, and management of metabolic risk factors²⁰²⁰ cardiovascular health, physical exercise, cognitive engagement, and management of metabolic risk factors
all supported by evidence regardless of genetic risk. For R47H carriers, aggressive management of these modifiable risk factors may be especially prudent given the elevated genetic risk.

Interactions — TREM2 and the Broader AD Landscape

TREM2 functions within a complex network of AD risk genes. The most important interaction is with APOE. TREM2 directly binds apolipoprotein E, and APOE lipidation status affects TREM2 activation²¹²¹ TREM2 directly binds apolipoprotein E, and APOE lipidation status affects TREM2 activation
APOE4 destabilizes the TREM2-apoE complex compared to APOE3. Studies suggest APOE4 homozygotes and TREM2 R47H carriers show greater tau pathology spreading from entorhinal cortex to neocortex²²²² APOE4 homozygotes and TREM2 R47H carriers show greater tau pathology spreading from entorhinal cortex to neocortex
indicating synergistic effects on disease progression.

TREM2 also interacts with other microglial genes. Variants in MS4A cluster genes, which also affect microglial function²³²³ MS4A cluster genes, which also affect microglial function
may compound with TREM2 effects on amyloid clearance. Similarly, PLCG2, another gene in the TREM2 signaling pathway²⁴²⁴ PLCG2, another gene in the TREM2 signaling pathway
shows protective variants that might partially offset TREM2 R47H risk.

The TREM2-APOE interaction warrants compound implication consideration. Research shows that carriers of both R47H and APOE4 face compounded risk and altered disease trajectory compared to either variant alone, with differential effects on microglial barrier formation around plaques and tau spreading.