More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk

Abstract

Over twenty risk loci have been identified for late onset Alzheimer’s disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4,567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (OR=7.40, P=3.66E-06). In addition to AD risk, we also examined the association of R47H with AD-related phenotypes, including age-at-onset, psychosis, and amyloid deposition, but found no significant association. Our results corroborate those of other studies implicating TREM2 as a LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration.

The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E

“…The significance of this association was subsequently confirmed in several additional studies and meta-analyses (9,(17)(18)(19). rs75932628 causes an R47H missense mutation in the TREM2 ectodomain.…”

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

“…Recently, the missense TREM2-R47H mutation has been identified and validated as a risk variant for LOAD (6,7,11,(15)(16)(17)(18)(19). Although numerous studies have investigated the genetic link between TREM2 variants and neurodegenerative diseases, only two other studies have empirically tested the functional outcome of disease-associated mutations (23,51).…”

Regulation of microglial survival and proliferation in health and diseases

“…Because of the dramatic early onset dementia and unique pathology observed in individuals with total loss of TREM2 signaling, it was surprising that recent genome wide association studies (GWAS) and more conventional sequencing studies found that heterozygousity for the rare TREM2 variant R47H is associated with a significantly increased odds ratio for the development of late-onset Alzheimer's disease (AD) [43–46]. Unlike the pathology in NHD, partial loss of TREM2 signaling resulted in individuals that are heterozygous for TREM2 R47H developing AD, which is characterized by deposition of amyloid-β (Aβ) plaques and hyper-phosphorylated tau tangles, which leads to the development of dementia [43–46].…”

“…Unlike the pathology in NHD, partial loss of TREM2 signaling resulted in individuals that are heterozygous for TREM2 R47H developing AD, which is characterized by deposition of amyloid-β (Aβ) plaques and hyper-phosphorylated tau tangles, which leads to the development of dementia [43–46]. We have recently demonstrated that, in a mouse model of AD, significantly more amyloid-β (Aβ) accumulated in the brains of TREM2-deficient than in those of TREM2-sufficient mice [27].…”