AbstractINTRODUCTIONMicroglial responses are an integral part of Alzheimer's disease (AD) pathology and are associated with amyloid beta (Aβ) deposition. This study aimed to investigate the effects of Aβ and microglial responses on global cognitive impairment.METHODSIn this longitudinal study, 28 patients with mild cognitive impairment and 11 healthy controls underwent 11C‐PK11195 and 11C‐Pittsburgh compound B positron emission tomography (PET), structural magnetic resonance imaging scans, and global cognitive ratings at baseline and 2‐year follow‐up. Correlations between PET uptake and global cognition were assessed. Additionally, the mediation effect of the microglial response on the association between Aβ load and global cognition was assessed.RESULTSAβ load and the microglial response were both independently detrimental to global cognitive performance at baseline; however, at 2‐year follow‐up the association between Aβ load and global cognitive ratings was partially mediated by the microglial response.DISCUSSIONAs AD progresses, the associated microglial response partially mediates the detrimental effect of aggregated Aβ on cognition.Highlights This was a longitudinal study of amyloid beta (Aβ), microglial responses, and global cognitive performance. Aβ and microglial responses both affect cognition in early Alzheimer's disease. Microglial response partially mediates the effect of Aβ on cognition in later stages.