ApoE4 is a major genetic risk determinant for Alzheimer's disease (AD) and drives its pathogenesis via A beta-dependent and -independent pathways. C/EBP beta, a proinflammatory cytokine-activated transcription factor, is upregulated in AD patients and increases cytokines and delta-secretase expression. Under physiological conditions, ApoE is mainly expressed in glial cells, but its neuronal expression is highly elevated under pathological stresses. However, how neuronal ApoE4 mediates AD pathologies remains incompletely understood. Here we show that ApoE4 activates C/EBP beta that subsequently regulates APP, Tau and BACE1 mRNA expression in mouse neurons, driving AD-like pathogenesis. To interrogate the pathological roles of both human ApoE4 and C/EBP beta elevation in neurons in the aged brain, we develop neuronal specific Thy1-ApoE4/C/EBP beta double transgenic mice. Neuronal ApoE4 strongly activates C/EBP beta and augmented 8-secretase subsequently cleaves increased mouse APP and Tau, promoting AD-like pathologies. Notably, Thy1-ApoE4/C/EBP beta mice develop amyloid deposits, Tau aggregates and neurodegeneration in an age-dependent manner, leading to synaptic dysfunction and cognitive disorders. Thus, our findings demonstrate that neuronal ApoE4 triggers AD pathogenesis via activating the crucial regulator C/EBP beta.