A Risk Variant rs6922617 in TREM Is Discrepantly Associated With Defining Neuropathological Hallmarks in the Alzheimer’s Continuum

Abstract The single nucleotide polymorphism (SNP)-rs6922617 in the triggering receptor expressed on myeloid cells (TREM) gene cluster is a potential risk factor for Alzheimer’s disease (AD). Here, we examined whether rs6922617 is associated with AD-defining neuropathological hallmarks and memory performance. We assessed the interaction between the variant rs6922617 and levels of beta-amyloid (Aβ), tau pathology, neurodegeneration, namely amyloid-tau-neurodegeneration framework, and cognition functions in 660 healthy controls, 794 mild cognitively impaired, and 272 subjects with AD. We employed linear regression and linear mixed models to examine the association. Here we find that the SNP-rs6922617 in the TREM gene cluster is associated with a higher global amyloid-ligands positron emission tomography (Aβ-PET) burden and lower fluorodeoxyglucose positron emission tomography (FDG-PET) load. Interestingly, rs6922617 risk allele carriers exhibit a significantly reduced tau accumulation compared to the non-carriers, indicating a discrepant association with Aβ and tau pathologies. Though the participants carrying the rs6922617 risk allele do not show a correlation with poorer cognitive performance, stronger neuropathological phenotypes, and memory impairments are evident in ApoE ε4 carriers with the rs6922617 risk allele. These results support the notion that the SNP-rs6922617 in the TREM gene cluster is associated with AD-related neuropathological hallmarks, such as Aβ and FDG-mediated neurodegeneration, rather than tau accumulation. Although the direct association with memory impairment in the Alzheimer’s continuum remains inconclusive, our findings suggest a potential role of rs6922617 in facilitating neuropathology hallmarks.