Soluble TREM2 mediates earliest amyloid-associated p-tau increases and cerebral glucose hypermetabolism in Alzheimer’s disease

Background Microglial activation occurs early in Alzheimer’s disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Therefore, it is critical to investigate at which AD stages microglial activation could be protective or detrimental to evaluate microglia as a treatment target. To address this, we used CSF sTREM2 (i.e. Triggering receptor expressed on myeloid cells 2) to investigate disease stage-dependent drivers of microglial activation and to determine downstream consequences on AD biomarker progression. Methods We included 402 cognitively normal and mild cognitively impaired patients with CSF sTREM2 assessments. To assess AD severity, we included measures of earliest beta-amyloid (i.e. Aβ) in CSF (i.e. Aβ 1-42 ) and late-stage fibrillary Aβ pathology (i.e. amyloid-PET centiloid), as well as p-tau 181 and FDG-PET for assessing downstream changes in tau and cerebral glucose metabolism. To determine disease stage, we stratified participants according to earliest Aβ abnormalities (i.e. Aβ CSF+/PET−; early Aβ-accumulators, n=70) or fully developed fibrillary Aβ pathology (i.e. Aβ CSF+/PET+; late Aβ-accumulators, n=201) plus 131 healthy controls (i.e. Aβ CSF−/PET−). Results In early Aβ-accumulators, higher centiloid was associated with cross-sectional/longitudinal sTREM2 and p-tau increases, suggesting reactive microglial and p-tau increases in response to earliest Aβ fibrillization. Further, higher sTREM2 mediated the association between centiloid and cross-sectional/longitudinal p-tau increases and higher sTREM2 was associated with FDG-PET hypermetabolism in line with previous findings of increased glucose consumption of activated microglia. In late Aβ-accumulators, we found no association between centiloid and sTREM2 but a cross-sectional association between higher sTREM2, higher p-tau and glucose hypometabolism, suggesting that sTREM2 parallels tau and neurodegeneration rather than Aβ once fully developed Aβ pathology is present. Conclusions Our findings suggest that sTREM2-related microglial activation occurs in response to earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p-tau increases in earliest AD, while previous reports of protective sTREM2 effects may occur in later AD stages.