ABSTRACT Selective elimination of early pathological TAU species may be a promising therapeutic strategy to reduce TAU accumulation that contributes to neurodegeneration and hallmarks Alzheimer disease (AD). By performing a genetic analysis of a cohort of 435 patients with AD, we defined the NDP52 GE variant (rs550510) of the autophagic receptor NDP52 (also known as CALCOCO2) as a protective factor for AD. We provide evidence that in in vitro systems and in a Drosophila melanogaster model of TAU-induced AD, NDP52 reduces the accumulation of pathological forms of TAU through the autophagic process and rescues typical neurodegenerative phenotypes induced by hTAU-toxicity. More importantly, we showed that the NDP52 GE variant is much more effective in this respect than NDP52 WT . Mechanistically, we showed that NDP52 directly binds pathological phospho-TAU, and that NDP52 WT and NDP52 GE bind them with comparable efficiency. On the contrary, we showed that NDP52 GE binds the autophagic machinery (LC3C and LC3B) more efficiently than NDP52 WT . We also showed for the first time that NDP52 is a direct target of protein phosphatase 2A (PP2A) in vitro , opening the way to the possibility that this phosphatase may fine-tune the autophagic function of NDP52 in AD. Finally, we found a positive correlation between the worldwide distribution of the allele encoding NDP52 GE and the incidence or prevalence of AD. Overall, our work highlights the variant NDP52 GE as a resilience factor in AD that shows a robust effectiveness to drive pathological TAU degradation.