Coding variants in TREM2 increase risk for Alzheimer's disease
Open accessAbstract
The triggering receptor expressed on myeloid 2 (TREM2) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous mutations in TREM2 cause Nasu-Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer''s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis, we performed pooled sequencing of TREM2 coding regions in 2082 AD cases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H [P = 9.17 × 10(-4), odds ratio (OR) = 2.63 (1.44-4.81)] and p.R62H [P = 2.36 × 10(-4), OR = 2.36 (1.47-3.80)] were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD [PSKAT-O = 5.37 × 10(-7); OR = 2.55 (1.80-3.67)]. The association of TREM2 variants with AD is still highly significant after excluding p.R47H [PSKAT-O = 7.72 × 10(-5); OR = 2.47 (1.62-3.87)], indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H (P = 4.65 × 10(-2)) and p.R62H (P = 6.87 × 10(-3)) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.
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Numerous TREM2 mutations linked with AD have been identified, including R47H, R62H, N68K, D87N, and T96K.
“Numerous TREM2 mutations linked with AD have been identified, including R47H, R62H, N68K, D87N, T96K, and so on.191,193”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [191]
The Results report significant AD-risk associations for R47H and R62H and identify D87N and T96K among the variants studied. They do not establish individual AD-risk associations for D87N or T96K, and N68K was not found in our copy (searched: N68K). (LLM, conf=0.90)
Experimental — accuracy not yet measuredBoth rare and common variants have been identified in core microglial genes, such as TREM2.
“Consistent with these enrichment analyses, both rare and common variants have been identified in core microglial genes, such as TREM213,14.”
From Variant-to-function mapping of late-onset Alzheimer’s disease GWAS signals in human microglial cell models implicates <i>RTFDC1</i> at the <i>CASS4</i> locus (2024) · cites this paper as [14]
The Discussion (page unavailable) identifies TREM2 as a gene expressed in brain microglia and reports rare TREM2 coding variants associated with Alzheimer’s disease risk. It does not identify common variants in TREM2 or other microglial genes, so this source supports only the rare-variant part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHomozygous TREM2 mutations are associated with Nasu-Hakola disease or frontotemporal dementia, while TREM2 variants associated with AD are heterozygous.
“Homozygous mutations are associated with Nasu–Hakola disease (NHD),189 or frontotemporal dementia,190 while the TREM2 variants associates with AD are heterozygous.191”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [191]
TREM2 variants associate with an increased risk of AD.
“Importantly, TREM2 variants associate with an increased risk of AD [15, 25, 38–40].”
From Protective PLCG2 variants associate with a delayed onset of Alzheimer’s disease among heterozygous APOE ε4 carriers (2026) · cites this paper as [40]
The enrichment of prioritized proteins in microglia and immune pathways supports a strong immunological role in AD, including TREM2, CD33, and IL34.
“supporting a strong immunological role in AD93–95 including TREM27,96, CD33, and IL34.”
From Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and implicates causal proteins for Alzheimer’s disease (2024) · cites this paper as [96]
Several other TREM2 variants (R62H, T66M, H157Y, D87N) increase the risk of AD.
“Several other TREM2 variants that affect the expression of TREM2 also increased the risk of AD, including R62H, T66M, H157Y, and D87N.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [166]
Additional rare variants in TREM2 have been associated with AD risk.
“Since the identification of R47H, additional rare variants in TREM2 have been associated with AD risk [138–140]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [139]
The R47H variant of TREM2 has an effect size for increased Alzheimer's disease risk comparable to the APOEε4 allele, around a 3-fold increased risk.
“The risk from this variant has a comparable effect size with the APOEε4 allele (around 3-fold increased AD risk; 4,19–22).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [20]
Further TREM2 variants such as R62H, H157Y, Q33X, T66M and Y38C are risk factors of Alzheimer's disease or other CNS diseases.
“In addition to the R47H variant, further TREM2 variants have been revealed to be risk factors of AD or other CNS diseases, such as R62H (8,20), H157Y (25), Q33X, T66M and Y38C (26,27).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [20]
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“Homozygous mutations are associated with Nasu–Hakola disease (NHD),(189) or frontotemporal dementia,(190) while the TREM2 variants associates with AD are heterozygous.(191) Different mutations in TREM2 seem to generate diverse affection on the function of it.”
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- Authors
- Jin, S. C., Benitez, B. A., Karch, C. M., Cooper, B., Skorupa, T., Carrell, D., Norton, J. B., Hsu, S., Harari, O., Cai, Y., Bertelsen, S., Goate, A. M., & Cruchaga, C.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Goate, Alison M.
- Cruchaga, Carlos
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2014-06-04
- Volume
- 23
- Issue
- 21
- Pages
- 5838-5846
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC4189899
- OpenAlex
- W2107590165
- Cited by
- 314
- References
- 46
- Citations by year
- 2026: 20 · 2025: 34 · 2024: 28 · 2023: 18 · 2022: 23 · 2021: 31 · 2020: 30 · 2019: 28 · 2018: 30 · 2017: 27 · 2016: 23 · 2015: 18 · 2014: 4
- FWCI
- 16.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Federation for Aging Research
- Alvin J. Siteman Cancer Center (CA91842, #P30 CA91842)
- Georgia Clinical and Translational Science Alliance (UL1TR000448)
- National Institutes of Health (NIH P50, UL1TR000448, 5p30ns069329-02, AG05681, AG 03991, CA91842, NS069329)
- National Institute on Aging (RF1AG044546, AG03991, K01AG046374, AG 05681, R01AG035083, U24 AG21886, P 50 AG05681, R01AG041797, R01AG044546, AG026276, P50AG005681, P01 AG0 3991, P01AG003991, AG035083, U24AG026395, U24AG056270, P01AG026276, U24AG021886)
- National Cancer Institute (P30 CA 91842, CA91842, P30CA091842)
- National Institute of Neurological Disorders and Stroke (P30-NS069329)
- National Center for Research Resources (P30 CA91842)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- TREM2, Alzheimer's disease, genetic risk variants, microglia, non-synonymous variants, Nasu-Hakola disease, soluble TREM2, gene-based association, European-American population
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, Amino Acid Sequence, Brain, Female, Humans, Male, Membrane Glycoproteins, Middle Aged, Molecular Sequence Data, Receptors, Immunologic, Risk, Genetic Variation, Case-Control Studies, Open Reading Frames, Sequence Alignment, Alternative Splicing, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Association Studies
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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