90: Sex, APOE-ε4 and TREM2: Who drives tau in medial temporal and neocortex?

Giorgio J et al., Nature Communications - A multi-cohort neuroimaging and genetics study (n=1,354) used PET and causal path modelling to test how sex, APOE-ε4 dosage and TREM2 rare variants influence stages of the canonical amyloid→tau cascade, focusing on entorhinal (EC) and neocortical (MetaTemp) tau. Key terms: APOE-ε4, TREM2, entorhinal tau, amyloid-beta, sex differences.

Study Highlights:
Using ADNI, A4 and HABS-HD cohorts, the authors show that females and APOE-ε4 homozygotes have greater entorhinal tau for a given level of amyloid-beta. APOE-ε4 homozygosity and TREM2 risk-variant carriership are linked to increased spread of tau from entorhinal cortex into neocortex. Interactions among APOE-ε4, TREM2 and sex modulate mediation along the Aβ→EC tau→MetaTemp tau pathway, with replication across cohorts.

Conclusion:
Genetic traits—female sex, APOE-ε4 homozygosity and TREM2 risk variants—produce heterogeneous effects at distinct stages of the amyloid-driven tau cascade: females and APOE-ε4 homozygotes are more susceptible to primary EC tau accumulation for a given Aβ burden, while APOE-ε4 homozygosity and TREM2 variants promote greater neocortical tau spread, with implications for individualized timing of anti-Aβ and anti-tau therapies.

Music:
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Article title:
Variable and interactive effects of Sex, APOE ε4 and TREM2 on the deposition of tau in entorhinal and neocortical regions

First author:
Giorgio J

Journal:
Nature Communications

DOI:
10.1038/s41467-025-60370-8

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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QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-07-29.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the canonical amyloid→tau cascade, genetic modifiers (sex, APOE-ε4, TREM2), their interactions with amyloid, and therapeutic implications; cross-checked against the canonical Nature Communications article.
- transcript topics: Sex differences in entorhinal cortex tau accumulation for a given amyloid level; APOE-ε4 dose effects on entorhinal and neocortical tau; TREM2 risk variants and microglial dysfunction in tau spread; Interactions: APOE-ε4 × Aβ and sex × Aβ on tau pathology; Clinical implications for anti-amyloid/anti-tau therapies and personalized medicine

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 4
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Canonical AD cascade: amyloid-β initiates tau accumulation in the entorhinal cortex (EC) and tau spreads to the neocortex
- Females show greater EC tau for a given level of amyloid than males
- APOE-ε...