Hippocampal hyperactivity is a precursor of Alzheimer disease and more prominent in APOE-ε4 carriers. It is therefore important to investigate the processes of hippocampal self-regulation, to monitor therapeutic efficacy of preclinical interventions. We have developed a closed-loop, virtual reality neurofeedback paradigm for real-time fMRI, that provides a standardized method for quantifying processes of hippocampal self-regulation. We acquired multi-modal neuroimaging data from a sample of 53 cognitively unimpaired subjects at risk for AD and applied standard methods of structural and functional connectomics. The analyses reveal significant negative associations between hippocampal CA1 down-regulation performance and APOE-ε4 alleles, as well as hippocampal streamline density volume. Better memory performance was associated with increased, bilateral hippocampal functional connectivity during the neurofeedback task. These are the first results to link neurofeedback performance to a genetic risk factor and structural connectivity. Further, these are the first evidence that functional cohesion between the hippocampi can reflect subtle differences in memory function, in cognitively unimpaired individuals at risk for AD. We provide a novel method to assess hippocampal function in preclinical AD, and propose it can be used to derive proxies for neural reserve.

The effect of APOE genotype and streamline density volume, on hippocampal CA1 down-regulation: a real-time fMRI virtual reality neurofeedback study