AbstractThe role of microglia in tau accumulation is currently unclear but could provide an important insight into the mechanisms underlying Alzheimer’s disease (AD)¹. Here, we measured the microglial marker soluble TREM2 and the disease-associated microglial activation stage 2 markers AXL, MERTK, GAS6, LPL, CST7, SPP1 and CSF1 in nondemented individuals from the Swedish BioFINDER-2 cohort who underwent longitudinal tau-positron emission tomography (PET), amyloid-PET and global cognitive assessment. To assess whether baseline microglial markers had an effect on AD-related changes, we studied three sub-groups of individuals: 121 with evidence of amyloid-PET pathology (A⁺), 64 with additional evidence of tau-PET pathology (A⁺T⁺) and 159 without amyloid- or tau-PET pathology (A⁻T⁻). Our results showed that increased levels of TREM2 were associated with slower amyloid accumulation in A⁺ individuals in addition to slower tau deposition and cognitive decline in A⁺T⁺ subjects. Similarly, higher levels of AXL, MERTK, GAS6, LPL, CST7 and CSF1 predicted slower tau accumulation and/or cognitive decline in the A⁺T⁺ group. These findings have important implications for future therapeutic strategies aiming to boost microglial protective functions in AD.