️ 90: Variable and Interactive Effects of Sex, APOE ε4 and TREM2 on Tau Deposition

️ Episode 90: Variable and Interactive Effects of Sex, APOE ε4 and TREM2 on Tau Deposition In this episode of PaperCast Base by Base, we explore how genetic factors—including sex differences, Apolipoprotein E ε4 allele dosage, and rare TREM2 risk variants—shape the accumulation and spread of tau pathology in Alzheimer’s disease using multimodal imaging and causal path analysis. Study Highlights:This multi-cohort investigation combined PET imaging and genetic data from over 1,300 participants across ADNI, A4, and HABS‑HD cohorts to model how amyloid-beta, entorhinal cortex tau, and genetics interact. Causal path modeling revealed that females and APOE ε4 homozygotes exhibit higher entorhinal tau for a given level of amyloid-beta. Rare TREM2 variant carriers displayed enhanced propagation of tau from entorhinal regions into the neocortex. Interactive effects between APOE ε4 and TREM2 further amplified neocortical tau burden. Conclusion:This study illuminates the roles of sex, APOE, and microglial genetics in tau pathology progression and underscores the need for personalized therapeutic timing targeting amyloid and tau in Alzheimer’s disease. Reference:Giorgio J, Jonson C, Wang Y, Yokoyama JS, Wang J, Jagust WJ, et al. Variable and interactive effects of sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions. Nature Communications. 2025;16:5812. doi:10.1038/s41467-025-60370-8 License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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