APOE genotype differentially modulates prion pathology in a mouse model.

APOE polymorphism affects the risk of occurrence and the rate of progression in several neurodegenerative diseases including Alzheimer’s disease, primary tauopathies, α-synucleinopathy, and age-related macular degeneration, but its role in prionoses remains unestablished. Using APOE targeted replacement (TR) mice, we investigated how APOE genotype affects key neurodegenerative mechanisms involved in prion pathology. Male and female ε2/ε2, ε3/ε3, and ε4/ε4 APOE-TR mice were inoculated with 22L mouse-adapted scrapie strain or normal brain homogenate and monitored with behavioral testing from 10-week post inoculation (wpi.) onward. Mice were euthanized at 23 wpi. when all prion-infected animals were symptomatic, and their brains were analyzed for multiple neuropathological, biochemical, and transcriptomic metrics. ε4/ε4(22L) mice featured the shortest disease latency time, the worst neurological score, and the highest load of spongiform lesions. ε2/ε2(22L) mice performed significantly better than ε4/ε4(22L) mice but significantly worse than ε3/ε3(22L) animals. Numerous aspects of PrP proteinopathy were exacerbated in the presence of the ε4 allele including increased PrP(Sc) accumulation, reduced PrP solubility, and increased PrP oligomerization. These metrics were comparable between ε2/ε2(22L) and ε3/ε3(22L) mice. Prion pathology significantly increased brain apolipoprotein (apo) E levels, with the greatest increase in ε4/ε4(22L) mice. All apoE isoforms formed complexes with conformationally altered PrP, but this interaction was the strongest in ε4/ε4(22L) mice. ε4/ε4(22L) mice had the highest load of reactive microglia and astrocytes and upregulation of transcriptomic markers typical of neurodegenerative microglia and astrocytes, followed by ε2/ε2(22L), with ε3/ε3(22L) having the lowest. Thus, APOE polymorphism differentially regulates the progression of prion pathology attributable to two ε4-affected mechanisms: increased conversion and accumulation of PrP(Sc) and worsened prion-associated neuroinflammation. Though less severely than ε4, the ε2 allele also increased the inflammatory response, rendering disease outcome worse relative to the ε3 allele. Our findings suggest both ε4 and ε2 alleles are disadvantageous determinants in prion pathology. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-025-02207-5.