APOE isoform‐associated tau oligomer polymorphs differ in synaptotoxicity and seeding activity

INTRODUCTION Pathological tau aggregates form distinct polymorphic species across diseases and even across Alzheimer's disease (AD) patients. However, tau aggregate polymorphism across the apolipoprotein E isoforms ( APOE ε2, ε3, ε4), the strongest predictors of late‐onset AD development, is unknown. METHODS This study assessed the conformational and bioactivity properties of tau oligomers from 14 patients with varying APOE genotypes. RESULTS Tau oligomers differ in proteolytic stability and cleavage site profiles across the APOE isoforms, indicating conformationally distinct polymorphs. APOE isoform‐associated tau oligomers affect synaptic plasticity differently, with ε4‐associated oligomers having the highest potency and strongest impact on synaptic functioning. Bioactivity assays reveal that ε4‐associated oligomers demonstrate particularly high seeding activity. Interestingly, tau oligomer synaptotoxicity and seeding activity are independent characteristics. DISCUSSION The APOE isoforms are associated with distinct tau oligomer polymorphs with varying bioactivity, underscoring the importance of considering APOE status when generating AD therapies. Polymorph‐specific targeting of pathological tau species could provide a novel method of combating AD. Highlights Conformational and bioactivity distinctions of tau oligomers have not yet been investigated across the APOE isoforms (ε2, ε3, ε4). Tau oligomers differ in conformational properties across the APOE isoforms. APOE ε4‐relevant tau oligomers strongly impair synaptic plasticity and demonstrate high tau seeding activity. APOE ε4‐relevant tau oligomers exist as a particularly toxic species, making them an ideal target for tau‐based AD therapies.