Current Biology
Volume 30, Issue 21, 2 November 2020, Pages 4201-4212.e3
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Article
Genetic Alzheimer’s Disease Risk Affects the Neural Mechanisms of Pattern Separation in Hippocampal Subfields

https://doi.org/10.1016/j.cub.2020.08.042Get rights and content
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Highlights

  • CA3 and DG perform pattern separation in a spatial mnemonic discrimination task

  • Pattern separation, but not novelty effects, are affected by APOE genotype

  • APOE-ε3-ε4 and APOE-ε3-ε2 carriers show differential recruitment of CA3 and DG

  • Investigating pattern separation has high potential for understanding early AD

Summary

The hippocampal subfields perform distinct operations during acquisition, differentiation, and recollection of episodic memories, and deficits in pattern separation are among the first symptoms of Alzheimer’s disease (AD). We investigated how hippocampal subfields contribute to pattern separation and how this is affected by Apolipoprotein-E (APOE), the strongest AD genetic risk factor. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), APOE-ε3-ε3 carriers predominantly recruited cornu ammonis 3 (CA3) during a spatial mnemonic discrimination task, whereas APOE-ε3-ε4 and APOE-ε3-ε2 carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, APOE-ε3-ε4 carriers showed reduced pattern separation in CA3, whereas APOE-ε3-ε2 carriers exhibited increased effects in DG and pattern separation-related functional connectivity between DG and CA3. Collectively, these results demonstrate that AD genetic risk alters hemodynamic responses in young pre-symptomatic individuals, paving the way for development of biomarkers for preclinical AD.

Keywords

pattern separation
episodic memory
APOE genotype
7T
hippocampal subfields
dentate gyrus
CA3
functional connectivity

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