The mechanism of widespread neuronal death occurring in Alzheimer's disease (AD) remains enigmatic even after extensive investigation during the last two decades. Amyloid beta 42 peptide (Aβ1-42) is believed to play a causative role in the development of AD. Here we expressed human Aβ1-42 and amyloid beta 40 (Aβ 1-40) in Drosophila neurons. Aβ1-42 but not Aβ1-40 causes an extensive accumulation of autophagic vesicles that become increasingly dysfunctional with age. Aβ1-42 -induced impairment of the degradative function, as well as the structural integrity, of post-lysosomal autophagic vesicles triggers a neurodegenerative cascade that can be enhanced by autophagy activation or partially rescued by autophagy inhibition. Compromise and leakage from post-lysosomal vesicles result in cytosolic acidification, additional damage to membranes and organelles, and erosive destruction of cytoplasm leading to eventual neuron death. Neuronal autophagy initially appears to play a pro-survival role that changes in an age-dependent way to a pro-death role in the context of Aβ1-42 expression. Our in vivo observations provide a mechanistic understanding for the differential neurotoxicity of Aβ 1-42 and Aβ1-40, and reveal an Aβ 1-42-induced death execution pathway mediated by an age-dependent autophagic-lysosomal injury.