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

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.