Extracellular amyloid plaques formed from aggregated Amyloid-β (Aβ), a specific cleavage product of Amyloid Precursor Protein (APP), and intracellular tau-containing neurofibrillary tangles are the two key histopathological hallmarks of Alzheimer’s Disease (AD). However, increasing evidence suggests that the trigger for neurodegeneration in AD involves intraneuronal defects in endolysosomes, which might be induced by both Aβ and tau. Recent high-resolution analysis of trafficking inside neuronal and non-neuronal cells suggests such defects may arise through aberrant compartmental maturation events during regulated secretion. These events bring together APP, secretory and endosomal compartments, and also the proteolytic secretases that generate Aβ. They may be initiated by the accumulation of Aβ and/or C-terminal fragments of APP, which interfere with endolysosomal trafficking and potentially induce tau pathology. They also lead to secretion of proteins from these Aβ-containing compartments, which can trigger endolysosomal phenotypes in other cells that endocytose them. By implicating regulated secretion in the initiation of AD, this new model highlights novel intracellular mechanisms that might drive neurodegeneration. Identifying suppressors of these pathways could suggest entry points for the development of novel therapies that target the earliest stages of AD pathology.