ArticleAlzheimer's & dementia : the journal of the Alzheimer's Association2025
APOE isoform-associated tau oligomer polymorphs differ in synaptotoxicity and seeding activity.
Article in Alzheimer's & dementia : the journal of the Alzheimer's Association, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- APOE isoform-associated tau oligomer polymorphs differ in synaptotoxicity and seeding activity.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
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10 authors.
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Abstract
introductionPathological 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.
methodsThis study assessed the conformational and bioactivity properties of tau oligomers from 14 patients with varying APOE genotypes.
resultsTau 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.
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