AbstractINTRODUCTIONTau and neurodegeneration strongly correlate with cognitive impairment, as compared to amyloid. However, their contribution in explaining cognition and predicting cognitive decline in memory clinics remains unclarified.METHODSWe included 94 participants with Mini‐Mental State Examination (MMSE), tau positron emission tomography (PET), amyloid PET, fluorodeoxyglucose (FDG) PET, and MRI scans from Geneva Memory Center. Linear regression and mediation analyses tested the independent and combined association between biomarkers, cognitive performance, and decline. Linear mixed‐effects and Cox proportional hazards models assessed biomarkers’ prognostic values.RESULTSMetabolism had the strongest association with cognition (r = 0.712; p < 0.001), followed by tau (r = ‐0.682; p < 0.001). Neocortical tau showed the strongest association with cognitive decline (r = ‐0.677; p < 0.001). Metabolism mediated the association between tau and cognition and marginally mediated the one with decline. Tau positivity represented the strongest risk factor for decline (hazard ratio = 32).DISCUSSIONTau and neurodegeneration synergistically contribute to global cognitive impairment while tau drives decline. The tau PET superior prognostic value supports its implementation in memory clinics.Highlights Hypometabolism has the strongest association with concurrent cognitive impairment. Neocortical tau pathology is the main determinant of cognitive decline over time. FDG‐PET has a superior value compared to MRI as a measure of neurodegeneration. The prognostic value of tau‐PET exceeded all other neuroimaging modalities.