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 A beta(1-42)) and late-stage fibrillary A beta pathology (amyloid-PET centiloid), as well as sTREM2, p-tau(181), and FDG-PET. To determine disease stage, we stratified participants into early A beta-accumulators (A beta CSF+/PET-; n = 70) or late A beta-accumulators (A beta CSF+/PET+; n = 201) plus 131 controls. In early A beta-accumulators, higher centiloid was associated with cross-sectional/longitudinal sTREM2 and p-tau(181) increases. Further, higher sTREM2 mediated the association between centiloid and cross-sectional/longitudinal p-tau(181) increases and higher sTREM2 was associated with FDG-PET hypermetabolism. In late A beta-accumulators, we found no association between centiloid and sTREM2 but a cross-sectional association between higher sTREM2, higher p-tau(181) and glucose hypometabolism. Our findings suggest that a TREM2-related microglial response follows earliest A beta fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p-tau(181) increases in earliest AD.