TREM2 variants in Alzheimer's disease

Abstract

Background: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.

Methods: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.

Results: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.

Conclusions: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).

Figure 1. Pathological Hallmarks in Carriers of TREM2 Variants

Shown are pathological findings in samples containing variant D87N (Panels A through D) and variant R47H (Panels E through L) obtained from patients with Alzheimer's disease. A carrier of the D87N variant had mature plaques (Panel A, arrow), along with more diffuse plaques and a moderate degree of cerebral amyloid angiopathy (Panel B). Beta amyloid was found deposited in leptomeningeal blood vessels. Tau immunohistochemical analysis revealed neuritic plaques (Panel C) in the hippocampus and numerous neurofibrillary tangles throughout the cortical regions (Panel D). Two carriers of the R47H variant also showed pathological features of Alzheimer's disease (with sections obtained from one patient in Panels E through H and from the other in Panels I through L) in the form of mature and diffuse plaques (Panels E and J, arrow). Severe cerebral amyloid angiopathy was evident with the presence of parenchymal capillary involvement (Panel F) and circumferential deposition of beta amyloid (Panel K). Also present were neuritic plaques (Panels G and L, arrow in Panel L), neurofibrillary tangles (Panels H and L), and abundant neuropil threads. However, one carrier of the R47H variant showed only moderate cerebral amyloid angiopathy with no other pathological abnormalities (Panel I, inset). Immunohistochemical analysis was carried out with the use of antibodies against beta amyloid (DAKO; 1:100) to identify the beta amyloid protein in both plaques and cerebral amyloid angiopathy, and AT8 antibody (Autogen Bioclear; 1:600) to identify tau.

Figure 2. Immunohistochemical Analyses of Trem2 in TgCRND8 Mice

Slides of samples from TgCRND8 mice (a transgenic mouse model of Alzheimer's disease) and age-matched littermates (controls) at different ages show that Trem2 is expressed as small granules in the cytoplasm of neurons (arrowheads) in both the transgenic mice and controls. In a slide of a sample from a transgenic mouse, the amyloid plaques are also surrounded by Trem2-positive granules (Panel D, arrow), and the Trem2 granules increase in number and size, as compared with the controls. The scale bar represents 30 mm in Panels A, B, C, E, and F and 60 mm in Panel D.