Identification of hippocampal volume as a mediator of the association between APOE4 and dementia

Objective: To identify any mediating effect of vascular and neurodegenerative risk factors of dementia in the association existing between APOE4 and dementia. Methods: 1,240 participants from the French Three City Dijon Study without prevalent tumor or dementia were included. Among these participants, 76 developed dementia during the 12 years of follow-up. Using regression and mediation analyses, we studied whether known risk factors for dementia i.e smoking status, body mass index, diabetes mellitus, hypercholesterolemia, hypertension, hippocampal volume, rate of hippocampal volume loss or white matter hyperintensities could mediate the association between APOE4 and dementia. Regression models were adjusted for age, sex, education level (and total intracranial volume when imaging metrics were considered). Results: Hippocampal volume was a partial mediator of the association between APOE4 and dementia (mediation ratio = 6.7%, p=0.03). No mediation effect was found for hypercholesterolemia. No mediation analyses could be undertaken for the others factors due to the lack of their association with APOE4 in our sample. Conclusions: In this study, the association between APOE4 and dementia was partially mediated by hippocampal volume, confirming a deleterious role of APOE4 in the hippocampus. This result warrants further replication in other cohorts, with higher sample sizes.