The TREM2 H157Y variant is associated with more severe neurodegeneration in Alzheimer's disease and altered immune-related processes

Abstract

Introduction: Multiple TREM2 variants are associated with an increased risk of Alzheimer's disease (AD). TREM2 H157Y is the only variant located at the proteolytic cleavage site that enhances TREM2 protein shedding. While this variant is associated with increased AD risk predominantly in the Chinese population, its impact on AD pathology is largely unknown.

Methods: We conducted an in-depth study integrating clinical cases, neuroimaging data, and blood proteomic data.

Results: TREM2 H157Y variant carriers with AD exhibit more severe AD pathology, more severe neurodegeneration, and more rapid clinical progression. Cognitively normal individuals carrying the variant show changes in blood proteins that are associated with neurodegeneration and inflammation. Moreover, the TREM2 H157Y variant is associated with altered immune and vascular processes irrespective of disease state.

Discussion: These findings highlight the clinical implications of the TREM2 H157Y variant and the use of blood proteomic data to investigate the effects of genetic variants on disease-related endophenotypes.

Highlights: The TREM2 H157Y variant is associated with more rapid clinical progression of Alzheimer's disease only in the presence of the apolipoprotein E (APOE) ε4 allele. The TREM2 H157Y variant is associated with neurodegeneration, irrespective of disease state. The TREM2 H157Y variant is associated with altered immune and vascular processes, irrespective of disease state. Cognitively normal TREM2 H157Y carriers show altered disease-associated blood proteins related to peripheral immune response. Blood proteomic data can be used to study the impacts of disease-associated genetic variants on disease outcomes and biological processes involved in pathogenesis.

Keywords: Alzheimer's disease; TREM2; blood biomarkers; clinical case study; genetic variant; neurodegeneration; peripheral immune.

FIGURE 1

Pedigree chart of the six families (in the genetic variant cohort) with TREM2 H157Y variant carriers. The color corresponds to their clinical diagnosis: red, orange, and black indicate AD, MCI, and CN, respectively. The second row shows the APOE genotype of each individual. * This individual is CN (with a MoCA score of 25) but was found to have AD pathology on neuroimaging (i.e., Aβ‐positive and tau‐positive on PET). Aβ, amyloid β; AD, Alzheimer's disease; APOE, apolipoprotein E; CN, cognitively normal; MCI, mild cognitive impairment; MoCA, Montreal Cognitive Assessment; PET, positron emission tomography; TREM2, triggering receptor expressed on myeloid cells 2.

FIGURE 2

Patients with AD carrying the TREM2 H157Y variant exhibit more severe disease‐related endophenotypes. (A) Adjusted MoCA scores of TREM2 H157Y variant carriers (GA) and non‐carriers (GG) who are CN or diagnosed with MCI or AD from Study Cohort_1. Data are presented as box‐and‐whisker plots; whiskers indicate minimum and maximum values. Statistical analysis was performed using two‐sample t‐test. *p < 0.05, **p < 0.01, *** p < 0.001. (B–D) Normalized volumes of (B) total gray matter, (C) cortex, and (D) subcortical gray matter of TREM2 H157Y variant carriers diagnosed with MCI and AD in Study Cohort_1. Data are presented as the normalized mean, with lower‐ and upper‐class limits retrieved from statistical analysis (Supplementary Method S4). *Adjusted p < 0.05, **adjusted p < 0.01, ***adjusted p < 0.001. (E, F) Plasma levels of (E) pTau217 and (F) NfL in TREM2 H157Y variant carriers and non‐carriers who are CN or diagnosed with MCI, or AD from Study Cohort_1. Data are presented as box‐and‐whisker plots; whiskers indicate minimum and maximum values. Statistical analysis was performed using two‐sample t‐test. *p < 0.05, **p < 0.01, ***p < 0.001. One value of plasma pTau217 in non‐carriers with AD is missing due to limited plasma volume. (G) Dot plot showing the association between plasma NfL level and age among TREM2 H157Y variant carriers and non‐carriers from Study Cohort_1. Simple linear regression analysis results are presented as regression lines. GG, slope (±standard error) = 0.863 (±0.122); GA, slope (±standard error) = 1.70 (±0.230). AD, Alzheimer's disease; CN, cognitively normal; MCI, mild cognitive impairment; MoCA, Adjusted Montreal Cognitive Assessment; NfL, neurofilament light polypeptide; TREM2, triggering receptor expressed on myeloid cells 2.

FIGURE 3

TREM2 H157Y variant carriers exhibit dysregulation of blood proteins associated with neurodegeneration and inflammation. (A) Volcano plot showing the association of blood proteins in the NULISAseq CNS Disease panel with the TREM2 H157Y variant among patients with AD from Study Cohort_2. Blue and red dots indicate blood proteins that are significantly (p < 0.05) downregulated and upregulated, respectively.(B–E) Plasma levels of (B) NfL, (C) NfH, (D) pTau231, and (E) pTau217 of TREM2 H157Y variant carriers and non‐carriers who are CN or diagnosed with AD from Study Cohort_2. Data are presented as box‐and‐whisker plots; whiskers indicate minimum and maximum values. Statistical analysis was performed using linear regression. *p < 0.05, **p < 0.01, ***p < 0.001. (F) Volcano plot showing the association of blood proteins in the NULISAseq CNS Disease panel with the TREM2 H157Y variant among CN individuals from Study Cohort_2. Blue and red dots indicate blood proteins that are significantly (p < 0.05) downregulated and upregulated, respectively. AD, Alzheimer's disease; CN, cognitively normal; NfH, neurofilament heavy polypeptide; NfL, neurofilament light polypeptide; TREM2, triggering receptor expressed on myeloid cells 2.

FIGURE 4

TREM2 H157Y variant carriers exhibit alterations in blood proteins associated with immune and vascular processes, and cognitively normal variant carriers exhibit dysregulation of disease‐related blood proteins. (A) Volcano plot showing the association of blood proteins in the Olink Target series panels with the TREM2 H157Y variant among patients with AD from Study Cohort_3. Blue and red dots indicate blood proteins that are significantly (p < 0.05) downregulated and upregulated, respectively. (B) Bar chart showing the top five GO biological processes altered in TREM2 H157Y variant carriers among patients with AD and CN individuals. (C) PPI network of blood proteins associated with the TREM2 H157Y variant among patients with AD. The top three downregulated and upregulated protein clusters are displayed. The functional enrichment of each cluster was retrieved from the STRING database (v12.0). (D) Volcano plot showing the association of blood proteins in the Olink Target series panels with the TREM2 H157Y variant among CN individuals from Study Cohort_3. Blue and red dots indicate blood proteins that are significantly (p < 0.05) downregulated and upregulated, respectively. (E) PPI network of blood proteins associated with the TREM2 H157Y variant among CN individuals. The top three upregulated protein clusters and the major downregulated protein cluster are displayed. The functional enrichment of each cluster was retrieved from the STRING database (v12.0). (F, G) Correlation analysis of the effects of (F) MCI and (G) AD on the blood proteomic profile and that of the H157Y variant on the blood proteomic profile among CN individuals. Blue and red dots indicate downregulated and upregulated blood proteins, respectively, that are significantly associated (p < 0.05) with the TREM2 H157Y variant in CN individuals. AD, Alzheimer's disease; CN, cognitively normal; GO, Gene Ontology; MCI, mild cognitive impairment; PPI, protein–protein interaction; TREM2, triggering receptor expressed on myeloid cells 2.