ApoE ε4 allele relateted alterations in hippocampal connectivity in early Alzheimer's disease support memory performance.

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 allele. 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 non-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 extra-DMN areas 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.