TREM2 – Alzheimer’s Disease

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose heterozygous variants confer increased risk for Alzheimer’s disease (Alzheimer disease). TREM2 (HGNC:17761) encodes a single‐pass transmembrane receptor that associates with the DAP12/TYROBP adaptor to mediate phagocytosis and inflammatory responses in the CNS. Rare coding substitutions in TREM2’s Ig‐like domain have emerged as moderate‐penetrance risk factors for late‐onset Alzheimer’s disease. The most extensively studied variant, c.140G>A (p.Arg47His), is enriched in AD versus controls in multiple cohorts and impairs ligand binding and microglial function.

Genetic association of TREM2 with Alzheimer’s disease was first reported in an Icelandic discovery series (OR 2.92; P = 3.42×10⁻¹⁰) and replicated in U.S., Norwegian, Dutch, and German case–control cohorts ([PMID:23150908]). Subsequent meta-analyses across 24 086 AD cases and 148 993 controls confirmed a highly significant association (OR 2.71; P = 4.67×10⁻²⁵) for rs75932628-T (p.Arg47His) ([PMID:25936935]). In Han Chinese populations, p.His157Tyr (c.469C>T) was also associated with AD risk (OR 3.65; 95% CI 1.61–8.28; P = 0.002) in a meta-analysis of 7 102 cases and 7 408 controls ([PMID:27501831]).

The spectrum of AD‐associated TREM2 variants has expanded beyond R47H to include missense changes such as p.His157Tyr, p.Arg62His and p.Ala192Thr (c.574G>A), as well as rarer substitutions in the Ig‐like domain. Case reports and family studies have implicated additional variants such as c.433G>T (p.Gly145Trp) and c.185G>A (p.Arg62His) in individual AD patients, often with functional corroboration. Although TREM2 risk alleles act in an incomplete‐penetrance, dose‐dependent manner, aggregate burden analyses demonstrate a significant enrichment of damaging TREM2 missense variants in AD cases versus controls.

Segregation evidence includes a large late-onset AD family in which 12 of 16 affected individuals carried the p.Arg47His variant (PMID:26076170), supporting co‐segregation with disease. Although no pure Mendelian inheritance has been established, these data underscore the semi‐dominant risk model. Family‐based and population‐based studies together document hundreds of heterozygous carriers of p.Arg47His and other risk alleles within AD‐affected kindreds and case–control cohorts.

Functional studies demonstrate that AD‐associated TREM2 variants compromise receptor maturation, surface expression, ligand binding, and microglial phagocytosis. Missense mutations such as p.Arg47His and p.Thr66Met reduce N‐linked glycosylation and impair recycling of TREM2 to the plasma membrane ([PMID:25615530, PMID:27717139]). Heterologous expression and iPSC‐derived microglia assays show markedly reduced cell‐surface levels and phagocytic uptake of lipoprotein–amyloid complexes by R47H‐bearing cells ([PMID:24990881, PMID:27345793]). Mouse models further reveal that Trem2 deficiency alters microglial chemotaxis, amyloid plaque compaction, and neuroinflammatory gene networks, corroborating human disease mechanisms ([PMID:39308178]).

Although no conflicting genetic evidence has substantially refuted the TREM2–AD association, allele frequency varies across ancestries and some non‐European cohorts show weaker replication, indicating population‐specific effects. Overall, genetic and functional data are concordant, with risk variants eliciting microglial dysfunction that plausibly accelerates neurodegeneration.

In summary, heterozygous TREM2 variants act as moderate‐penetrance risk factors for Alzheimer’s disease through a haploinsufficiency mechanism that impairs microglial clearance and inflammatory regulation. Additional rare variants continue to be identified, but the core p.Arg47His allele has reached strong evidence thresholds. Key Take‐Home: TREM2 genetic screening, particularly for p.Arg47His and p.His157Tyr, can inform AD risk stratification and guide microglia‐targeted therapeutic development.

References

• The New England Journal of Medicine • 2013 • Variant of TREM2 associated with the risk of Alzheimer’s disease. PMID:23150908
• Alzheimer's & Dementia • 2015 • The role of TREM2 R47H variant as a risk factor for early-onset Alzheimer’s disease. PMID:25936935
• Current Neurovascular Research • 2016 • TREM2 p.H157Y Variant and the Risk of Alzheimer's Disease: A Meta-Analysis Involving 14,510 Subjects. PMID:27501831
• Science Translational Medicine • 2014 • TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. PMID:24990881
• Acta Neuropathologica Communications • 2016 • Rare TREM2 variants associated with Alzheimer's disease display reduced cell surface expression. PMID:27589997
• JAMA Neurology • 2015 • R47H Variant of TREM2 Associated With Alzheimer Disease in a Large Late-Onset Family: Clinical, Genetic, and Neuropathological Study. PMID:26076170

Evidence Based Scoring (AI generated)