Background
Genetics of TREM2 in NDDs
Diverse TREM2 variants are associated with NDD risk
TREM2 variants are the genetic basis of PLOSL and some familial FTD cases
TREM2 variants are associated with risk for AD
TREM2 variants have been investigated as risk factors for other NDDs
The epidemiology of TREM2 variants
The relationship between TREM2 and other NDD genetic risk factors
TREM2 expression
Co-regulation of TREM2 and other members of the TREM family
Regulation of TREM2 expression
Cell types in which TREM2 is expressed
TREM2 expression changes throughout neurodevelopment and varies across brain regions
Inflammatory stimuli, injury and disease drive changes in TREM2 expression
TREM2 expression by peripherally derived macrophages in the AD brain
TREM2 structure and signaling
The structure of full-length TREM2
The structure and production of soluble TREM2
Subcellular localization of TREM2
TREM2 ligands
TREM2 associates with the intracellular adaptor DAP12
TREM2 signaling downstream of DAP12
Other TREM2 signaling complexes
Biological actions of sTREM2
TREM2 function
TREM2 regulates myeloid cell number
TREM2 enhances myeloid cell survival
TREM2 enhances myeloid cell proliferation and differentiation
TREM2 regulates myeloid cell chemotaxis
TREM2 regulates phagocytic function
TREM2 modulates inflammatory responses
Other functions of TREM2
TREM2 and NDD pathology
TREM2 impacts amyloid pathology in AD
TREM2 modulates neuritic dystrophy in AD
TREM2 affects tau hyperphosphorylation and aggregation in AD
TREM2 affects synaptic and neuronal loss in AD
The effect of TREM2 on other NDD pathologies
The effect of TREM2 on inflammation-related pathologies
The clinical relevance of TREM2
TREM2-related biomarkers
Study | Sample Type | Method of sTREM2 Detection | Main Finding (p-value) | sTREM2 (pg/ml), mean ± sd or median(IQR) | Study Cohort | Controls (CTR) | Diagnostic Parameters | Age (yrs) mean ± sd or Median(range) | Gender (percent female) | ApoE ε4+ carriers | ||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Criteria | Cognitive Testing | Other | ||||||||||
Gispert et al. (2016) [316] | CSF | ELISA | ↑ sTREM2 [CTR-MCI (0.01); PreAD-MCI (0.036); CTR-AD (0.044)] |
Relat. to IS
CTR: 400 ± 200 PreAD: 530 ± 390 MCI: 710 ± 420 AD: 620 ± 400 | PreAD (n = 19), MCI due to AD (n = 27), and mild AD (n = 23); all non-TREM2 variant carriers | Cognitively normal subjects defined by MMSE score > 27, CDR = 0, and negative AD CSF profilea (n = 45) | NIA-AA for AD and MCI due to AD groups | MMSE and CDR; PreAD had MMSE score > 27 and CDR = 0 | MRI; Positive AD CSF profile: Aβ42 (<500 pg/ml), t-tau (>450 pg/ml), and p-tau (>75 pg/ml) | CTR: 60.98 ± 6.83 PreAD: 68.53 ± 7.93 MCI: 70.30 ± 7.35 AD: 66.78 ± 9.75 | CTR: 63% PreAD:68% MCI: 55% AD: 69% | CTR: 15% PreAD:42% MCI: 52% AD: 48% |
Suárez-Calvet et al. (2016) [202] | CSF | ELISA | ↑ sTREM2 [CTR-MCI (0.002); AD-MCI (0.013); PreAD-MCI (0.062)] |
Relat. to IS
CTR: 470 ± 202 PreAD: 644 ± 410 MCI: 802 ± 380 AD: 725 ± 440 | PreAD (n = 63), MCI due to AD (n = 111), and AD (n = 200), from five centers | Asymptomatic cognitively normal subjects with a negative AD CSF profilea, determined across five centers (n = 150) | NIA-AA for each group | NR | Positive AD CSF profilea with cut-off values unique to each center (refer to [322]) | CTR: 62.4 ± 11 PreAD: 70.8 ± 11 MCI: 74.3 ± 9 AD: 73.8 ± 10 | CTR: 59% PreAD:60% MCI: 60% AD: 62% | CTR: 21% PreAD:58% MCI: 52% AD: 62% |
Suárez-Calvet et al. (2016) [12] | CSF | ELISA | ↑ sTREM2 [NC-MC (0.004)] | NC: 2824 ± 1292 MC: 3561 ± 1661 | Cases with ADAD (n = 127) from DIAN cohort | Noncarriers (n = 91) for ADAD-related mutations from DIAN cohort | Presence of ADAD mutation (PSEN1, PSEN2, or APP) assessed by DIAN | MMSE and CDR | AD CSF profile examined | NC: 39.5 ± 11 MC: 40.4 ± 11 | NC: 54% MC: 50% | NC: 34% MC: 28% |
↑ sTREM2 [MC with CDR = 0.5 (0.006); MC with CDR = 1 (0.044)] | No. of Subjects per CDR: CDR n
0 52 0.5 51 1 16 2 to 3 8 | No. of Subjects per CDR: CDR n 0 88 0.5 3 1 0 2 to 3 0 | ||||||||||
Heslegrave et al. (2016) [314] | CSF | Novel reaction monitoring assay with UPLC/TQ-S MS | ↑ sTREM2 [CTR-AD (0.0457)] | CTR: 195.6 (131.0–240.7) AD: 231.2 (172.5–305.4) |
UK cohort: AD (n = 37) | Cognitively normal with negative AD CSF profilea (n = 22) | Revised IWG2 for AD | MMSE | Positive AD CSF profilea (Aβ42 < 550 pg/ml, t-tau >375 pg/ml, p-tau >52 pg/ml) | CTR: 69.2 ± 8.0 AD: 70.51 ± 7.5 | CTR: 45% AD: 53% | CTR: 33% AD: 67% |
↑ sTREM2 [CTR-AD (0.0312)] | CTR: 171 (153.5–241.5) AD: 230 (166.5–297.4) |
Swedish cohort:
AD (n = 24) | Cognitively normal subjects (n = 16) | NIA-AA for AD or MCI due to AD | MMSE | MRI or CT; Blood screening (unspecified) | CTR: 55.6 ± 9.7 AD: 64.3 ± 6.8 | CTR: 56% AD: 54% | CTR: 31% AD: 69% | |||
Kleinberger et al. (2014) [225] | CSF | ELISA | ↓ sTREM2 [CTR-AD (0.001)] |
Relat. Values CTR: 0.381 (0.283–0.518) AD: 0.309 (0.178–0.436) | AD (n = 56), from AD-confirmed cases across six centers | Cognitively normal with negative AD CSF profilea (CSF: n = 88; plasma: n = 86) | NINCDS-ADRDA for probable AD | NR | Positive AD CSF profilea defined by the Mattsson et al. equation: [324] (Aβ42/p-tau)/(3.694 + 0.0105 x t-tau) | CTR: 60.7 ± 9.5 AD: 70.4 ± 8.9 | CTR: 63% AD: 68% | NR |
Plasma | ↔ sTREM2 [CTR-AD (0.872)] |
Relat. Values
CTR: 1.022 (0.675–1.864) AD: 0.998 (0.702–1.375) | AD (n = 51), from AD confirmed cases across six centers | CTR: 60.4 ± 9.5 AD: 70.7 ± 9.0 | CTR: 64% AD: 71% | NR | ||||||
Henjum et al. (2016) [203] | CSF | ELISA | ↔ sTREM2 [CTR-MCI (0.42); CTR-AD (0.17)] | CTR: 4400 (3000–5700) MCI: 4100 (2400–5900) AD: 4800 (3500–7100) |
Norwegian cohort:
AD (n = 29) or MCI due to AD (n = 21) | Cognitively normal subjects (n = 50) | DSM-IIIR for dementia; NINCDS-ADRDA for AD | MMSE | MRI or CT | CTR: 66 (50–86) MCI: 67 (55–75) AD: 68 (56–75) | CTR: 50% MCI: 57% AD: 45% | CTR: 0% MCI: 38% AD: 34.5% |
↔ sTREM2 [CTR-AD (0.76)] | CTR: 3200 (2800–5000) AD: 3800 (2600–5600) |
Swedish cohort:
AD (n = 25) | Cognitively normal with normal Aβ42 levels (>550 pg/ml) (n = 25) | NIA-AA for AD or MCI due to AD | MMSE | MRI or CT; Blood screening (unspecified) | CTR: 62 (43–80) AD: 79 (61–86) | CTR: 68% AD: 72% | CTR: 4% AD: 16% | |||
Piccio et al. (2016) [86] | CSF | ELISA | ↑ sTREM2 [CTR-AD (0.015)] | CTR: 1028 (244–2570) AD: 832 (163–2196) | Those with mainly mild AD, non-TREM2 variant carriers (CSF: n = 73; plasma: NR), from two centers | Cognitively normal subjects (CDR 0) and negative for AD CSF profilea (CSF: n = 107; plasma: NR) | NINCDS-ADRDA for probable AD | CDR | NR | CTR: 70.2 ± 8.5 AD: 76.6 ± 5.2 | CTR: 53% AD: 49% | CTR: 48% AD: 64% |
Plasma | ↔ sTREM2 [CTR-AD (0.74)] | CTR: 976 (65–2477) AD: 1019 (190–2546) | NR | NR | NR |