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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. We scanned young healthy participants at average, high, and low AD-risk during a spatial mnemonic discrimination task using ultra-high field (7T) functional magnetic resonance imaging (fMRI). Average AD-risk carriers predominantly recruited CA3 for the task, while high and low AD-risk carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, high AD-risk carriers showed reduced pattern separation in CA3, while low AD-risk carriers exhibited increased effects in DG and pattern separation-related CA3-DG functional connectivity. These results demonstrate that AD genetic risk alters hemodynamic responses in young asymptomatic individuals, paving way for development of biomarkers for preclinical AD.