The etiology of late onset Alzheimer’s disease is likely multifactorial, with aging being the biggest risk factor and genetic predisposition likely accelerating the disease onset. While in the rare early-onset familial AD dominant mutations lead to excessive neuronal production of the longest form of beta-amyloid (Ab42) in LOAD it remains to be established if Ab42 production increases. Ab42 is produced intracellularly upon APP processing in endosomes and controlled by the trafficking of APP and its secretases. Endosomal trafficking dysfunction has been suggested as a putative causal mechanism of LOAD. We are investigating the mechanisms whereby LOAD risk factors and neuronal aging alter endocytic trafficking to potentiate Aβ42 production. We analyzed wild-type primary mouse cortical neurons matured or aged in culture using a sensitive cell biological and neurobiological approach to determine APP and BACE1 trafficking alterations, and their impact on the Aβ42 production. We have discovered that AD patients’ mutations affect Bin1 and CD2AP function increase Aβ42 endocytic production, recapitulating the impact of Bin1 and CD2AP knockdown impact on BACE1 recycling and APP sorting to lysosomal degradation, suggesting their loss of function. Importantly, we discovered that neuronal aging alone potentiates APP clathrin and actin-mediated endocytosis, increasing intracellular Aβ42. Our results highlight the importance of endocytic trafficking defects, driven by genetic risk factors and aging, as a causal mechanism of late-onset Alzheimer’s disease.