sTREM2 is associated with amyloid-related p-tau increases and glucose hypermetabolism in Alzheimer's disease

Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage-dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta-amyloid (CSF Aβ1-42 ) and late-stage fibrillary Aβ pathology (amyloid-PET centiloid), as well as sTREM2, p-tau181 , and FDG-PET. To determine disease stage, we stratified participants into early Aβ-accumulators (Aβ CSF+/PET-; n = 70) or late Aβ-accumulators (Aβ CSF+/PET+; n = 201) plus 131 controls. In early Aβ-accumulators, higher centiloid was associated with cross-sectional/longitudinal sTREM2 and p-tau181 increases. Further, higher sTREM2 mediated the association between centiloid and cross-sectional/longitudinal p-tau181 increases and higher sTREM2 was associated with FDG-PET hypermetabolism. In late Aβ-accumulators, we found no association between centiloid and sTREM2 but a cross-sectional association between higher sTREM2, higher p-tau181 and glucose hypometabolism. Our findings suggest that a TREM2-related microglial response follows earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p-tau181 increases in earliest AD.