Genetic Alzheimer’s Disease Risk Affects the Neural Mechanisms of Pattern Separation in Hippocampal Subfields

• Published in: Current biology Vol. 30; no. 21; pp. 4201 - 4212.e3
• Main Authors: Lee, Hweeling, Stirnberg, Rüdiger, Wu, Sichu, Wang, Xin, Stöcker, Tony, Jung, Sonja, Montag, Christian, Axmacher, Nikolai
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 02.11.2020
• Subjects: APOE genotype; CA3; dentate gyrus; episodic memory; functional connectivity; hippocampal subfields; pattern separation; episodic memory; dentate gyrus; hippocampal subfields; functional connectivity; CA3; pattern separation; 7T; APOE genotype
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2020.08.042

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. •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 Lee et al. show that APOE-ε3-ε3 carriers mainly recruit CA3 during a relational pattern separation task. APOE-ε3-ε4 carriers demonstrate reduced pattern separation effects in the dentate gyrus, and APOE-ε3-ε2 carriers show enhanced pattern separation effects in the CA3 and increased pattern separation-related DG-CA3 functional connectivity.