Presenilin1 (PSEN1) E280A mutation causes early onset Alzheimer’s disease (AD) in the world’s largest familial AD kindred. We previously published a case report of a carrier from this kindred who was remarkably protected from cognitive decline for thirty years. Positron emission tomography (PET) brain analysis showed lower levels of Tau pathology relative to typical PSEN1 E280A carriers. Whole-genome sequencing revealed homozygosity for an Apolipoprotein E mutation (Christchurch, APOECh). As the ApoECh mutation is found within the heparan sulfate proteoglycan (HSPG) binding domain, we hypothesized that the cognitive protection was mediated by reduced binding of ApoE to HSPGs. However, it is possible that alternative complementary mechanisms might be mediated by ApoECh: thus, we sought to determine additional processes influenced by the ApoECh mutation. Hence, we performed single cell RNA sequencing of iPS-derived cerebral organoids from a non-protected PSEN1E280A carrier and from the PSEN1E280A/APOECh protected carrier. Additionally, we performed pull downs of mouse brain tissue using His-tagged ApoE and ApoECh recombinant proteins and identified interactors via mass spectrometry. Target validation was performed via immunoprecipitation, in vitro reporter assay and ELISA. Results indicated the presence of differentially expressed genes in APOECh cerebral organoids associated with the regulation of the Wnt/β-catenin signaling pathway. These experiments demonstrated that ApoECh: 1) enhances Wnt signaling and 2) preferably interacts with Tau over their ApoEWT counterparts. In conclusion, our research suggests that ApoECh acts through multiple mechanisms of protection that include both gain and loss of function which could inform future therapeutic approaches.