Background: Whether the presence of the Apolipoprotein E ε4 allele modulates hippocampal
connectivity networks in abnormal ageing has yet to be fully clarified.
Objective: Allele-dependent differences in this pattern of functional connectivity were investigated in
patients with very mild neurodegeneration of the Alzheimer’s type, carriers and non-carriers of the ε4
Method: A seed-based connectivity approach was used. The two groups were similar in demographics,
volumetric measures of brain structure, and cognitive profiles.
Results: ε4-carriers had increased connectivity between the seed area in the left hippocampus and 1) a
left insular/lateral prefrontal region and 2) the contralateral right parietal cortex. Moreover, hippocampus-
to-parietal connectivity in the group of ε4 carriers was positively associated with memory performance,
indicating that the between-group difference reflects compensatory processes. Retrospective
analyses of functional connectivity based on patients from the ADNI initiative confirmed this pattern.
Conclusion: We suggest that increased connectivity with areas external to the Default Mode Network
(DMN) reflects both compensatory recruitment of additional areas, and pathological interwining
between the DMN and the salience network as part of a global ε4-dependent circuital disruption. These
differences indicate that the ε4 allele is associated with a more profound degree of DMN network breakdown
even in the prodromal stage of neurodegeneration.